Substituted N-[(aminoiminomethyl or aminomethyl)phenyl]propyl amides

ABSTRACT

This invention relates to compounds of formula                    
     which inhibit Factor Xa, to pharmaceutical compositions containing the compounds, and to the use of the compounds for the treatment of patients suffering from conditions which can be ameliorated by the administration of an inhibitor of Factor Xa.

This application is a continuation application of International PatentApplication No. PCT/US98/13550 filed Jun. 26, 1998, which, in turn, is acontinuation-in-part application of U.S. patent application Ser. No08/884,405 filed Jun. 27, 1997,now U.S. Pat. No. 6/080,767 whichapplication claims priority benefit under 35 U.S.C. §371 ofInternational Patent Application No. PCT/US96/20770 filed Dec. 23, 1996,which, in turn, claims priority benefit of U.S. Provisional PatentApplication No. 60/009,485 filed Jan. 2, 1996.

FIELD OF THE INVENTION

The compounds of formula I exhibit useful pharmacological activity andaccordingly are incorporated into pharmaceutical compositions and usedin the treatment of patients suffering from certain medical disorders.More especially, they are Factor Xa inhibitors. The present invention isdirected to compounds of formula I, compositions containing compounds offormula I, and their use, which are for treating a patient sufferingfrom, or subject to, conditions which can be ameliorated by theadministration of an inhibitor of Factor Xa.

Factor Xa is the penultimate enzyme in the coagulation cascade. Bothfree factor Xa and factor Xa assembled in the prothrombinase complex(Factor Xa, factor Va, calcium and phospholipid) are inhibited bycompounds of formula I. Factor Xa inhibition is obtained by directcomplex formation between the inhibitor and the enzyme and is thereforeindependent of the plasma co-factor antithrombin III. Effective factorXa inhibition is achieved by administering the compounds either by oraladministration, continuous intravenous infusion, bolus intravenousadministration or any other parenteral route such that it achieves thedesired effect of preventing the factor Xa induced formation of thrombinfrom prothrombin.

Anticoagulant therapy is indicated for the treatment and prophylaxis ofa variety of thrombotic conditions of both the venous and arterialvasculature. In the arterial system, abnormal thrombus formation isprimarily associated with arteries of the coronary, cerebral andperipheral vasculature. The diseases associated with thromboticocclusion of these vessels principally include acute myocardialinfarction (AMI), unstable angina, thromboembolism, acute vessel closureassociated with thrombolytic therapy and percutaneous transluminalcoronary angioplasty (PTCA), transient ischemic attacks, stroke,intermittent claudication and bypass grafting of the coronary (CABG) orperipheral arteries. Chronic anticoagulant therapy may also bebeneficial in preventing the vessel luminal narrowing (restenosis) thatoften occurs following PTCA and CABG, and in the maintenance of vascularaccess patency in long-term hemodialysis patients. With respect to thevenous vasculature, pathologic thrombus formation frequently occurs inthe veins of the lower extremities following abdominal, knee and hipsurgery (deep vein thrombosis, DVT). DVT further predisposes the patientto a higher risk of pulmonary thromboembolism. A systemic, disseminatedintravascular coagulopathy (DIC) commonly occurs in both vascularsystems during septic shock, certain viral infections and cancer. Thiscondition is characterized by a rapid consumption of coagulation factorsand their plasma inhibitors resulting in the formation oflife-threatening clots throughout the microvasculature of several organsystems. The indications discussed above include some, but not all, ofthe possible clinical situations where anticoagulant therapy iswarranted. Those experienced in this field are well aware of thecircumstances requiring either acute or chronic prophylacticanticoagulant therapy.

SUMMARY OF THE INVENTION

This invention is directed to a compound of formula I:

is a single or double bond;

R_(a) is hydrogen, hydroxy or amino:

R₁ and R₂ are hydrogen or taken together are=NR₉;

R₃ is hydrogen, —CO₂R₆,—C(O)R₆,—CONR₆R₆,—CH₂OR₇ or —CH₂SR₇;

R₄ is hydrogen, alkyl, Q-alkyl or thioheterocyclyl, or a group offormula

R₅ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl,heterocyclenyl, fused arylcycloalkyl, fused heteroarylcycloalkyl, fusedarylcycloalkenyl, fused heteroarylcycloalkenyl, fused arylheterocyclyl,fused heteroarylheterocyclyl, fused arylheterocyclenyl, fusedheteroarylheterocyclenyl, aryl, fused cycloalkenylaryl, fusedcycloalkylaryl, fused heterocyclylaryl, fused heterocyclenylaryl,heteroaryl, fused cycloalkylheteroaryl, fused cycloalkenylheteroaryl,fused heterocyclenylheteroaryl, fused heterocyclylheteroaryl, aralkyl,heteroaralkyl, aralkenyl, heteroaralkenyl, aralkynyl or heteroaralkynyl;

R₆ is hydrogen or lower alkyl;

R₇ is hydrogen, lower alkyl, Ar(lower alkyl), lower acyl, aroyl orheteroaroyl;

R₈ is hydrogen or lower alkyl;

R₉ is hydrogen, R₁₀O₂C—, R₁₀O—, HO—, cyano, R₁₀CO—, HCO—, lower alkyl,nitro, or Y^(1a)Y^(2a)N—;

R₁₀ is alkyl, aralkyl, or heteroaralkyl;

Y^(1a) and Y^(2a) are independently hydrogen or alkyl;

A and B are hydrogen or taken together are a bond;

Q is R₇O— or R₇S—or Y¹Y²N—;

Y¹ and Y² are independently hydrogen, alkyl, aryl, and aralkyl, or oneof Y¹ and Y² is acyl or aroyl and the other of Y¹ and Y² is hydrogen,alkyl, aryl, and aralkyl;

Ar is aryl or heteroaryl; and

n is 0,1 or 2; or

a pharmaceutically acceptable salt thereof, a solvate thereof, orprodrug thereof.

DETAILED DESCRIPTION OF THE INVENTION

As used above, and throughout the description of the invention, thefollowing terms, unless otherwise indicated, shall be understood to havethe following meanings:

Definitions

“Patient” includes both human and other mammals.

“Alkyl” means an aliphatic hydrocarbon group which may be straight orbranched having about 1 to about 15 carbon atoms in the chain. Preferredalkyl groups have 1 to about 12 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl are attached to a linear alkyl chain. “Lower alkyl” means about 1to about 6 carbon atoms in the chain which may be straight or branched.The alkyl group may be substituted by one or more halo, cycloalkyl orcycloalkenyl. Representative alkyl groups include methyl, fluoromethyl,difluoromethyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl,ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, 3-pentyl, heptyl,octyl, nonyl, decyl and dodecyl.

“Alkenyl” means an aliphatic hydrocarbon group containing acarbon-carbon double bond and which may be straight or branched havingabout 2 to about 15 carbon atoms in the chain. Preferred alkenyl groupshave 2 to about 12 carbon atoms in the chain; and more preferably about2 to about 6 carbon atoms in the chain. Branched means that one or morelower alkyl groups such as methyl, ethyl or propyl are attached to alinear alkenyl chain. “Lower alkenyl” means about 2 to about 4 carbonatoms in the chain which may be straight or branched. The alkenyl groupmay be substituted by one or more halo. Representative alkenyl groupsinclude ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl,n-pentenyl, heptenyl, octenyl and decenyl.

“Alkynyl” means an aliphatic hydrocarbon group containing acarbon-carbon triple bond and which may be straight or branched havingabout 2 to about 15 carbon atoms in the chain. Preferred alkynyl groupshave 2 to about 12 carbon atoms in the chain; and more preferably about2 to about 4 carbon atoms in the chain. Branched means that one or morelower alkyl groups such as methyl, ethyl or propyl are attached to alinear alkynyl chain. “Lower alkynyl” means about 2 to about 4 carbonatoms in the chain which may be straight or branched. Representativealkynyl groups include ethynyl, propynyl, n-butynyl, 2-butynyl,3-methylbutynyl, n-pentynyl, heptynyl, octynyl and decynyl.

“Cycloalkyl” means a non-aromatic mono- or multicyclic ring system ofabout 3 to about 10 carbon atoms, preferably of about 5 to about 10carbon atoms. Preferred cycloalkyl rings contain about 5 to about 6 ringatoms. The cycloalkyl is optionally substituted with one or more “ringsystem substituents” which may be the same or different, and are asdefined herein. Representative monocyclic cycloalkyl includecyclopentyl, cyclohexyl, cycloheptyl, and the like. Representativemulticyclic cycloalkyl include 1-decalin, norbornyl, adamantyl, and thelike.

“Cycloalkenyl” means a non-aromatic mono or multicyclic ring system ofabout 3 to about 10 carbon atoms, preferably of about 5 to about 10carbon atoms which contains at least one carbon-carbon double bond.Preferred cycloalkylene rings contain about 5 to about 6 ring atoms. Thecycloalkenyl is optionally substituted with one or more “ring systemsubstituents” which may be the same or different, and are as definedherein. Representative monocyclic cycloalkenyl include cyclopentenyl,cyclohexenyl, cycloheptenyl, and the like. A representative multicycliccycloalkenyl is norbornylenyl.

“Heterocyclenyl” means a non-aromatic monocyclic or multicyclic ringsystem of about 3 to about ring atoms, preferably about 5 to about 10ring atoms, in which one or more of the atoms in the ring system is/areelement(s) other than carbon, for example nitrogen, oxygen or sulfuratoms, and which contains at least one carbon-carbon double bond orcarbon-nitrogen double bond. Preferred heterocyclenyl rings containabout 5 to about 6 ring atoms. The prefix aza, oxa or thia beforeheterocyclenyl means that at least a nitrogen, oxygen or sulfur atomrespectively is present as a ring atom. The heterocyclenyl is optionallysubstituted by one or more ring system substituents, wherein “ringsystem substituent” is as defined herein. The nitrogen or sulphur atomof the heterocyclenyl is optionally oxidized to the correspondingN-oxide, S-oxide or S,S-dioxide. Representative monocyclicazaheterocyclenyl groups include 1,2,3,4- tetrahydropyridine,1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridine,1,4,5,6-tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl,2-imidazolinyl, 2-pyrazolinyl, and the like. Representativeoxaheterocyclenyl groups include 3,4-dihydro-2H-pyran, dihydrofuranyl,fluorodihydrofuranyl, and the like. A representative multicyclicoxaheterocyclenyl group is 7-oxabicyclo[2.2.1]heptenyl. Representativemonocyclic thiaheterocyclenyl rings include dihydrothiophenyl,dihydrothiopyranyl, and the like

“Heterocyclyl” means a non-aromatic saturated monocyclic or multicyclicring system of about 3 to about 10 ring atoms, preferably about 5 toabout 10 ring atoms, in which one or more of the atoms in the ringsystem is/are element(s) other than carbon, for example nitrogen, oxygenor sulfur. Preferred heterocyclyls contain about 5 to about 6 ringatoms. The prefix aza, oxa or thia before heterocyclyl means that atleast a nitrogen, oxygen or sulfur atom respectively is present as aring atom. The heterocyclyl is optionally substituted by one or more“ring system substituents” which may be the same or different, and areas defined herein. The nitrogen or sulphur atom of the heterocyclyl isoptionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Representative monocyclic heterocyclyl rings includepiperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl,thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl,tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.

“Aryl” means an aromatic monocyclic or multicyclic ring system of 6 toabout 14 carbon atoms, preferably of about 6 to about 10 carbon atoms.The aryl is optionally substituted with one or more “ring systemsubstituents” which may be the same or different, and are as definedherein. Representative aryl groups include phenyl and naphthyl.

“Heteroaryl” means an aromatic monocyclic or multicyclic ring system ofabout 5 to about 14 ring atoms, preferably about 5 to about 10 ringatoms, in which one or more of the atoms in the ring system is/areelement(s) other than carbon, for example nitrogen, oxygen or sulfur.Preferred heteroaryls contain about 5 to about 6 ring atoms. The“heteroaryl” is optionally substituted by one or more “ring systemsubstituents” which may be the same or different, and are as definedherein. The prefix aza, oxa or thia before heteroaryl means that atleast a nitrogen, oxygen or sulfur atom respectively is present as aring atom. A nitrogen atom of a heteroaryl is optionally oxidized to thecorresponding N-oxide. Representative heteroaryls include pyrazinyl,furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl,oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl,triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl,phthalazinyl, imidazo[1,2-a]pyridine, imidazo[2,1-b]thiazolyl,benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl,quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, benzothiazolyl and the like.

“Fused arylcycloalkenyl” means a radical derived from a fused aryl andcycloalkenyl as defined herein by removal of hydrogen atom from thecycloalkenyl portion. Preferred fused arylcycloalkenyls are thosewherein aryl is phenyl and the cycloalkenyl consists of about 5 to about6 ring atoms. The fused arylcycloalkenyl is optionally substituted byone or more ring system substituents, wherein “ring system substituent”is as defined herein. Representative fused arylcycloalkenyl include1,2-dihydronaphthylene, indene, and the like, in which the bond to theparent moiety is through a non-aromatic carbon atom.

“Fused cycloalkenylaryl” means a radical derived from a fusedarylcycloalkenyl as defined herein by removal of hydrogen atom from thearyl portion. Representative fused cycloalkenylaryl are as describedherein for a fused arylcycloalkenyl, except that the bond to the parentmoiety is through an aromatic carbon atom.

“Fused arylcycloalkyl” means a radical derived from a fused aryl andcycloalkyl as defined herein by removal of a hydrogen atom from thecycloalkyl portion. Preferred fused arylcycloalkyls are those whereinaryl is phenyl and the cycloalkyl consists of about 5 to about 6 ringatoms. The fused arylcycloalkyl is optionally substituted by one or morering system substituents, wherein “ring system substituent” is asdefined herein. Representative fused arylcycloalkyl includes1,2,3,4-tetrahydronaphthyl, and the like, in which the bond to theparent moiety is through a non-aromatic carbon atom.

“Fused cycloalkylaryl” means a radical derived from a fusedarylcycloalkyl as defined herein by removal of a hydrogen atom from thearyl portion. Representative fused cycloalkylaryl are as describedherein for a fused arylcycloalkyl radical, except that the bond to theparent moiety is through an aromatic carbon atom.

“Fused arylheterocyclenyl” means a radical derived from a fused aryl andheterocyclenyl as defined herein by removal of a hydrogen atom from theheterocyclenyl portion. Preferred fused arylheterocyclenyls are thosewherein aryl is phenyl and the heterocyclenyl consists of about 5 toabout 6 ring atoms. The prefix aza, oxa or thia before theheterocyclenyl portion of the fused arylheterocyclenyl means that atleast a nitrogen, oxygen or sulfur atom respectively is present as aring atom. The fused arylheterocyclenyl is optionally substituted by oneor more ring system substituents, wherein “ring system substituent” isas defined herein. The nitrogen or sulphur atom of the heterocyclenylportion of the fused arylheterocyclenyl is optionally oxidized to thecorresponding N-oxide, S-oxide or S,S-dioxide. Representative fusedarylheterocyclenyl include 3H-indolinyl, 1H-2-oxoquinolyl,2H-1-oxoisoquinolyl, 1,2-dihydroquinolinyl, 3,4-dihydroquinolinyl,1,2-dihydroisoquinolinyl, 3,4-dihydroisoquinolinyl, and the like, inwhich the bond to the parent moiety is through a non-aromatic carbonatom.

“Fused heterocyclenylaryl” means a radical derived from a fusedarylheterocyclenyl as defined herein by removal of a hydrogen atom fromthe aryl portion. Representative fused heterocyclenylaryl are as definedherein for a fused arylheterocyclenyl radical, except that the bond tothe parent moiety is through an aromatic carbon atom.

“Fused arylheterocyclyl” means a radical derived from a fused aryl andheterocyclyl as defined herein by removal of a hydrogen atom from theheterocyclyl portion. Preferred fused arylheterocyclyls are thosewherein aryl is phenyl and the heterocyclyl consists of about 5 to about6 ring atoms. The prefix aza, oxa or thia before heterocyclyl means thatat least a nitrogen, oxygen or sulfur atom respectively is present as aring atom. The fused arylheterocyclyl is optionally substituted by oneor more ring system substituents, wherein “ring system substituent” isas defined herein. The nitrogen or sulphur atom of the heterocyclylportion of the fused arylheterocyclyl is optionally oxidized to thecorresponding N-oxide, S-oxide or S,S-dioxide. Representative preferredfused arylheterocyclyl ring systems include phthalimide,1,4-benzodioxane, indolinyl, 1,2,3,4-tetrahydroisoquinoline,1,2,3,4-tetrahydroquinoline, 1H-2,3-dihydroisoindolyl,2,3-dihydrobenz[f]isoindolyl, 1,2,3,4-tetrahydrobenz[g]isoquinolinyl,and the like, in which the bond to the parent moiety is through anon-aromatic carbon atom.

“Fused heterocyclylaryl” means a radical derived from a fusedaryheterocyclyl as defined herein by removal of a hydrogen atom from theheterocyclyl portion. Representative preferred fused heterocyclylarylring systems are as described for fused arylheterocyclyl, except thatthe bond to the parent moiety is through an aromatic carbon atom.

“Fused heteroarylcycloalkenyl” means a radical derived from a fusedheteroaryl and cycloalkenyl as defined herein by removal of a hydrogenatom from the cycloalkenyl portion. Preferred fusedheteroarylcycloalkenyls are those wherein the heteroaryl and thecycloalkenyl each contain about 5 to about 6 ring atoms. The prefix aza,oxa or thia before heteroaryl means that at least a nitrogen, oxygen orsulfur atom respectively is present as a ring atom. The fusedheteroarylcycloalkenyl is optionally substituted by one or more ringsystem substituents, wherein “ring system substituent” is as definedherein. The nitrogen atom of the heteroaryl portion of the fusedheteroarylcycloalkenyl is optionally oxidized to the correspondingN-oxide. Representative fused heteroarylcycloalkenyl include5,6-dihydroquinolyl, 5,6-dihydroisoquinolyl, 5,6-dihydroquinoxalinyl,5,6-dihydroquinazolinyl, 4,5-dihydro-1H-benzimidazolyl,4,5-dihydrobenzoxazolyl, and the like, in which the bond to the parentmoiety is through a non-aromatic carbon atom.

“Fused cycloalkenylheteroaryl” means a radical derived from a fusedheteroarylcycloalkenyl as defined herein by removal of a hydrogen atomfrom the heteroaryl portion. Representative fused cycloalkenylheteroarylare as described herein for fused heteroaylcycloalkenyl, except that thebond to the parent moiety is through an aromatic carbon atom.

“Fused heteroarylcycloalkyl” means a radical derived from a fusedheteroaryl and cycloalkyl as defined herein by removal of a hydrogenatom from the cycloalkyl portion. Preferred fused heteroarylcycloalkylsare those wherein the heteroaryl thereof consists of about 5 to about 6ring atoms and the cycloalkyl consists of about 5 to about 6 ring atoms.The prefix aza, oxa or thia before heteroaryl means that at least anitrogen, oxygen or sulfur atom is present respectively as a ring atom.The fused heteroarylcycloalkyl is optionally substituted by one or morering system substituents, wherein “ring system substituent” is asdefined herein. The nitrogen atom of the heteroaryl portion of the fusedheteroarylcycloalkyl is optionally oxidized to the correspondingN-oxide. Representative fused heteroarylcycloalkyl include5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydroisoquinolyl,5,6,7,8-tetrahydroquinoxalinyl, 5,6,7,8-tetrahydroquinazolyl,4,5,6,7-tetrahydro-1H-benzimidazolyl, 4,5,6,7-tetrahydrobenzoxazolyl,1H-4-oxa-1,5-diazanaphthalen-2-onyl,1,3-dihydroimidizole-[4,5]-pyridin-2-onyl, and the like, in which thebond to the parent moiety is through a non-aromatic carbon atom.

“Fused cycloalkylheteroaryl” means a radical derived from a fusedbeteroarylcycloalkyl as defined herein by removal of a hydrogen atomfrom the heteroaryl portion. Representative fused cycloalkylheteroarylare as described herein for fused heteroarylcycloalkyl, except that thebond to the parent moiety is through an aromatic carbon atom.

“Fused heteroarylheterocyclenyl” means a radical derived from a fusedheteroaryl and heterocyclenyl as defined herein by the removal of ahydrogen atom from the heterocyclenyl portion. Preferred fusedheteroarylheterocyclenyls are those wherein the heteroaryl thereofconsists of about 5 to about 6 ring atoms and the heterocyclenylconsists of about 5 to about 6 ring atoms. The prefix aza, oxa or thiabefore heteroaryl or heterocyclenyl means that at least a nitrogen,oxygen or sulfur atom is present respectively as a ring atom. The fusedheteroarylheterocyclenyl is optionally substituted by one or more ringsystem substituents, wherein “ring system substituent” is as definedherein. The nitrogen atom of the heteroaryl portion of the fusedheteroarylheterocyclenyl is optionally oxidized to the correspondingN-oxide. The nitrogen or sulphur atom of the heterocyclenyl portion ofthe fused heteroarylheterocyclenyl is optionally oxidized to thecorresponding N-oxide, S-oxide or S,S-dioxide. Representative fusedheteroarylheterocyclenyl include 7,8-dihydro[1,7]naphthyridinyl,1,2-dihydro[2,7]naphthyridinyl, 6,7-dihydro-3H-imidazo[4,5-c]pyridyl,1,2-dihydro 1,5-naphthyridinyl, 1,2-dihydro-1,6-naphthyridinyl,1,2-dihydro-1,7-naphthyridinyl,1,2-dihydro-1,8-naphthyridinyl,1,2-dihydro-2,6-naphthyridinyl, and the like, in which the bond to theparent moiety is through a non aromatic carbon atom.

“Fused heterocyclenylheteroaryl” means a radical derived from a fusedheteroarylheterocyclenyl as defined herein by the removal of a hydrogenatom from the heteroaryl portion. Representative fusedheterocyclenylheteroaryl are as described herein for fusedheteroarylheterocyclenyl, except that the bond to the parent moiety isthrough an aromatic carbon atom.

“Fused heteroarylheterocyclyl” means a radical derived from a fusedheteroaryl and heterocyclyl as defined herein, by removal of a hydrogenatom from the heterocyclyl portion. Preferred fusedheteroarylheterocyclyls are those wherein the heteroaryl thereofconsists of about 5 to about 6 ring atoms and the heterocyclyl consistsof about 5 to about 6 ring atoms. The prefix aza, oxa or thia before theheteroaryl or heterocyclyl portion of the fused heteroarylheterocyclylmeans that at least a nitrogen, oxygen or sulfur atom respectively ispresent as a ring atom. The fused heteroarylheterocyclyl is optionallysubstituted by one or more ring system substituents, wherein “ringsystem substituent” is as defined herein. The nitrogen atom of theheteroaryl portion of the fused heteroarylheterocyclyl is optionallyoxidized to the corresponding N-oxide. The nitrogen or sulphur atom ofthe heterocyclyl portion of the fused heteroarylheterocyclyl isoptionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Representative fused heteroarylheterocyclyl include2,3-dihydro-1H pyrrol[3,4-b]quinolin-2-yl, 1,2,3,4-tetrahydrobenz[b][1,7]naphthyridin-2-yl, 1,2,3,4-tetrahydrobenz[b][1,6]naphthyridin-2-yl, 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-2yl,1,2,3,4tetrahydro-9H-pyrido[4,3-b]indol-2yl,2,3,-dihydro-1H-pyrrolo[3,4-b]indol-2-yl,1H-2,3,4,5-tetrahydroazepino[3,4-b]indol-2-yl,1H-2,3,4,5-tetrahydroazepino[4,3-b]indol-3-yl,1H-2,3,4,5-tetrahydroazepino[4,5-b]indol-2yl,5,6,7,8-tetrahydro[1,7]napthyridinyl,1,2,3,4-tetrhydro[2,7]naphthyridyl,2,3-dihydro[1,4]dioxino[2,3-b]pyridyl,2,3-dihydro[1,4]dioxino[2,3-b]pryidyl,3,4-dihydro-2H-1-oxa[4,6]diazanaphthalenyl,4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridyl,6,7-dihydro[5,8]diazanaphthalenyl, 1,2,3,4-tetrahydro[1,5]napthyridinyl,1,2,3,4-tetrahydro[1,6]napthyridinyl, 1,2,3,4-tetrahydro[1,7]napthyridinyl,1,2,3,4-tetrahydro[1,8]napthyridinyl,1,2,3,4-tetrahydro[2,6]napthyridinyl, and the like, in which the bond tothe parent moiety is through a non-aromatic carbon atom.

“Fused heterocyclylheteroaryl” means a radical derived from a fusedheteroarylheterocyclyl as defined herein, by removal of a hydrogen atomfrom the heteroaryl portion. Representative fused heterocyclylheteroarylare as described herein for fused heterarylheterocyclyl, except that thebond to the parent moiety is through an aromatic carbon atom.

“Aralkyl” means an aryl-alkyl- group in which the aryl and alkyl are aspreviously described. Preferred aralkyls contain a lower alkyl moiety.Representative aralkyl groups include benzyl, 2-phenethyl andnaphthlenemethyl.

“Aralkenyl” means an aryl-alkenyl- group in which the aryl and alkenylare as previously described. Preferred aralkenyls contain a loweralkenyl moiety. Representative aralkenyl groups include 2-phenethenyland 2-naphthylethenyl.

“Aralkynyl” means an aryl-alkynyl- group in which the aryl and alkynylare as previously described. Preferred aralkynyls contain a loweralkynyl moiety. Representative aralkynyl groups include phenacetylenyland naphthylacetylenyl.

“Heteroaralkyl” means an heteroaryl-alkyl- group in which the heteroaryland alkyl are as previously described. Preferred heteroaralkyls containa lower alkyl moiety. Representative aralkyl groups includepyridylmethyl, 2-(furan-3-yl)ethyl and quinolin-3-ylmethyl.

“Heteroaralkenyl” means an heteroaryl-alkenyl- group in which theheteroaryl and alkenyl are as previously described. Preferredheteroaralkenyls contain a lower alkenyl moiety. Representativeheteroaralkenyl groups include 2-(pyrid-3-yl)ethenyl and2-(quinolin-3-yl)ethenyl.

“Heteroaralkynyl” means an heteroaryl-alkynyl- group in which theheteroaryl and alkynyl are as previously described. Preferredheteroaralkynyls contain a lower alkynyl moiety. Representativeheteroaralkynyl groups include pyrid-3-ylacetylenyl andquinolin-3-ylacetylenyl.

“Hydroxyalkyl” means a HO-alkyl- group in which alkyl is as previouslydefined. Preferred hydroxyalkyls contain lower alkyl. Representativehydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.

“Acyl” means an H—CO— or alkyl-CO— group in which the alkyl group is aspreviously described. Preferred acyls contain a lower alkyl.Representative acyl groups include formyl, acetyl, propanoyl,2-methylpropanoyl, butanoyl and palmitoyl.

“Aroyl” means an aryl-CO— group in which the aryl group is as previouslydescribed. Representative groups include benzoyl and 1- and 2-naphthoyl.

“Heteroaroyl” means a heteroaryl-CO— group in which the heteroaryl groupis as previously described. Representative groups include nicotinoyl andpyrrol-2-ylcarbonyl and 1- and 2-naphthoyl.

“Alkoxy” means an alkyl-O— group in which the alkyl group is aspreviously described. Representative alkoxy groups include methoxy,ethoxy, n-propoxy, i-propoxy, n-butoxy and heptoxy.

“Aryloxy” means an aryl-O— group in which the aryl group is aspreviously described. Representative aryloxy groups include phenoxy andnaphthoxy.

“Aralkyloxy” means an aralkyl-O— group in which the aralkyl groups is aspreviously described. Representative aralkyloxy groups include benzyloxyand 1- or 2-naphthalenemethoxy.

“Alkylthio” means an alkyl-S— group in which the alkyl group is aspreviously described. Representative alkylthio groups includemethylthio, ethylthio, i-propylthio and heptylthio.

“Arylthio” means an aryl-S— group in which the aryl group is aspreviously described. Representative arylthio groups include phenylthioand naphthylthio.

“Aralkylthio” means an aralkyl-S— group in which the aralkyl group is aspreviously described. A representative aralkylthio group is benzylthio.

“Y¹Y²N—” means a substituted or unsubstituted amino group, wherein Y¹and Y² are as previously described. Representative groups include amino(H₂N—), methylamino, ethylmethylamino, dimethylamino and diethylamino.

“Alkoxycarbonyl” means an alkyl-O—CO— group. Representativealkoxycarbonyl groups include methoxy- and ethoxycarbonyl.

“Aryloxycarbonyl” means an aryl-O—CO— group. Representativearyloxycarbonyl groups include phenoxy- and naphthoxycarbonyl.

“Aralkoxycarbonyl” means an aralkyl-O—CO— group. A representativearalkoxycarbonyl group is benzyloxycarbonyl.

“Y¹Y²NCO—” means a substituted or unsubstituted carbamoyl group, whereinY¹ and Y² are as previously described. Representative groups arecarbamoyl (H₂NCO—) and dimethylaminocarbamoyl (Me₂NCO—).

“Y¹Y²NSO₂—” means a substituted or unsubstituted sulfamoyl group,wherein Y¹ and Y² are as previously described. Representative groups aresulfamoyl (H₂NSO₂—) and dimethylsulfamoyl (Me₂NSO₂—).

“Alkylsulfonyl” means an alkyl-SO₂— group. Preferred groups are those inwhich the alkyl group is lower alkyl.

“Alkylsulfinyl” means an alkyl-SO— group. Preferred groups are those inwhich the alkyl group is lower alkyl.

“Arylsulfonyl” means an aryl-SO₂— group.

“Arylsulfinyl” means an aryl-SO— group.

“Halo” means fluoro, chloro, bromo, or iodo. Preferred are fluoro,chloro or bromo, and more preferred are fluoro or chloro.

“Ring system substituent” means a substituent attached which optionallyreplaces hydrogen on an aromatic or non-aromatic ring system. Ringsystem substituents are selected from the group consisting of aryl,heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroaralkyl,heteroaralkenyl, heteroaralkynyl, hydroxy, hydroxyalkyl, alkoxy,aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy,alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl,arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl,heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio,heteroaralkylthio, cycloalkyl, cycloalkenyl, heterocyclyl,heterocyclenyl, aryldiazo, heteroaryldiazo, amidino, Y¹Y²N—,Y¹Y²N-alkyl-, Y¹Y²NCO— or Y¹Y²NSO₂—, wherein Y¹ and Y² are independentlyhydrogen, alkyl, aryl, and aralkyl, or where the substituent is Y¹Y²N—or Y¹Y²N-alkyl- then one of y¹ and Y² is acyl or aroyl and the other ofY¹ and Y² is hydrogen, alkyl, aryl, and aralkyl. When a ring system issaturated or partially saturated, the “ring system substituent” furthercomprises methylene (H₂C═), oxo (O═) and thioxo (S═). acylamino,aroylamino,.

“Solvate” means a physical association of a compound of this inventionwith one or more solvent molecules. This physical association involvesvarying degrees of ionic and covalent bonding, including hydrogenbonding. In certain instances the solvate will be capable of isolation,for example when one or more solvent molecules are incorporated in thecrystal lattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolable solvates. Representative solvates includeethanolates, methanolates, and the like. “Hydrate” is a solvate whereinthe solvent molecule(s) is/are H₂O.

“Prodrug” means a form of the compound of formula I suitable foradministration to a patient without undue toxicity, irritation, allergicresponse, and the like, and effective for their intended use, includingketal, ester and zwitterionic forms. A prodrug is transformed in vivo toyield the parent compound of the above formula, for example byhydrolysis in blood. A thorough discussion is provided in T. Higuchi andV. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S.Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers inDrug Design, American Pharmaceutical Association and Pergamon Press,1987, both of which are incorporated herein by reference.

Preferred Embodiments

A preferred embodiment of the invention is a method for treating adisease state capable of being modulated by inhibiting production ofFactor Xa to a patient suffering from said disease state an effectiveamount of the compound of formula I .

A preferred compound aspect of the invention is the compound of formulaI wherein is a single bond.

A preferred compound aspect of the invention is the compound of formulaI wherein is a double bond.

A preferred compound aspect of the invention is the compound of formulaI wherein R_(a) is hydrogen.

A preferred compound aspect of the invention is the compound of formulaI wherein R_(a) is hydroxy or amino; more preferred is hydroxy.

A preferred compound aspect of the invention is the compound of formulaI wherein R₁ and R₂ taken together are ═NR₉.

Another preferred compound aspect of the invention is the compound offormula I wherein R₁ and R₂ taken together are ═NH.

A preferred compound aspect of the invention is the compound of formulaI wherein R₃ is hydrogen.

A preferred compound aspect of the invention is the compound of formulaI wherein R₃ is —CO₂R₆, —C(O)R₆, —CH₂OR₇ or —CH₂SR₇; more preferred is—CO₂R₆, —CH₂OR₇ or —CH₂SR₇; yet more preferred is —CO₂R₆ or —CH₂OR₇.

Another preferred compound aspect of the invention is the compound offormula I wherein R₃ is —CO₂R₆ and R₆ is lower alkyl.

Another preferred compound aspect of the invention is the compound offormula I wherein R₃ is —CH₂OR₇ or —CH₂SR₇ and R₇ is hydrogen or loweralkyl.

A preferred compound aspect of the invention is the compound of formulaI wherein R₄ is hydrogen, alkyl or Q-alkyl, or a group of formula

Another preferred compound aspect of the invention is the compound offormula I wherein R₄ is lower alkyl or a group of formula

where A and B are hydrogen and n is 1.

A preferred compound aspect of the invention is the compound of formulaI wherein R₄ is Q-alkyl.

Another preferred compound aspect of the invention is the compound offormula I wherein R₄ is R₇O(lower alkyl)—.

A preferred compound aspect of the invention is the compound of formulaI wherein R₄ is thioheterocyclyl.

A preferred compound aspect of the invention is the compound of formulaI wherein R₅ is alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl,heterocyclenyl, fused arylcycloalkyl, fused heteroarylcycloalkyl, fusedarylcycloalkenyl, fused heteroarylcycloalkenyl, fused arylheterocyclyl,fused heteroarylheterocyclyl, fused arylheterocyclenyl, fusedheteroarylheterocyclenyl, fused cycloalkenylaryl, fused cycloalkylaryl,fused heterocyclylaryl, fused heterocyclenylaryl, fusedcycloalkylheteroaryl, fused cycloalkenylheteroaryl, fusedheterocyclenylheteroaryl, fused heterocyclylheteroaryl, aralkyl,heteroaralkyl, aralkenyl, heteroaralkenyl, aralkynyl or heteroaralkynyl;more preferred is fused cycloalkenylaryl, fused cycloalkylaryl, fusedheterocyclylaryl, fused heterocyclenylaryl, fused cycloalkylheteroaryl,fused cycloalkenylheteroaryl, fused heterocyclenylheteroaryl or fusedheterocyclylheteroaryl.

Another preferred compound aspect of the invention is the compound offormula I wherein R₅ is cycloalkyl, heterocyclyl, aralkyl or aralkynyl.

A preferred compound aspect of the invention is the compound of formulaI wherein R₅ is aryl or heteroaryl.

Another preferred compound aspect of the invention is the compound offormula I wherein R₅ is phenyl, naphthyl, or heteroaryl.

Another preferred compound aspect of the invention is the compound offormula I wherein R₅ is phenyl substituted phenyl, heteroarylsubstituted phenyl, phenyl substituted heteroaryl or optionallyheteroaryl substituted heteroaryl.

Another preferred compound aspect of the invention is the compound offormula I wherein R₆ is lower alkyl.

Another preferred compound aspect of the invention is the compound offormula I wherein R₇ is hydrogen or lower alkyl.

A preferred compound aspect of the invention is the compound of formulaI wherein R₇ is Ar(lower alkyl) or heteroaroyl.

Another preferred compound aspect of the invention is the compound offormula I wherein R₈ is hydrogen.

Another preferred compound aspect of the invention is the compound offormula I wherein R₉ is hydrogen.

A preferred compound aspect of the invention is the compound of formulaI wherein A, B, R₈ and R₉ are hydrogen.

Another preferred compound aspect of the invention is the compound offormula I wherein R₁₀ is lower alkyl.

A preferred compound aspect of the invention is the compound of formulaI wherein Q is R₇O—.

A preferred compound aspect of the invention is the compound of formulaI wherein n is 1.

Another preferred compound aspect of the invention is the compound offormula I wherein the

moiety is in the meta position to the position of attachment of thephenyl moiety to the

moiety.

Another preferred compound aspect of the invention is the compound offormula I wherein the R_(a) is hydroxy or amino, more preferablyhydroxy, which is in the para position to the

moiety which is in the meta position to the position of attachment ofthe phenyl moiety to the

moiety.

Another preferred compound aspect of the invention is the compound offormula I wherein Ar is aryl.

Another preferred compound aspect of the invention is the compound offormula I wherein Ar is phenyl.

Included within the scope of formula I are compounds wherein R₁ and R₂taken together are ═NR₉, wherein R₉ is R₁₀O₂C—, R₁₀O—, cyano, R₁₀CO—,optionally substituted lower alkyl, nitro, or Y¹Y²N—. Such derivativesmay themselves comprise the biologically active compound useful fortreating a disease state capable of being modulated by inhibitingproduction of Factor Xa to a patient suffering from said disease state,or may act as pro-drugs to such biologically active compounds which areformed therefrom under physiological conditions.

Species according to the invention are selected from the following:

(Z)-N-[3-(5-Carbamimidoyl-2-hydroxyphenyl)allyl]-4-pyridin-3-ylbenzamide;

N-[3-(5-Carbamimidoyl-2-hydroxyphenyl)-propyl]-4-pyridin-3-yl)-benzamnideditrifluoroacetate;

N-[3-(5-Carbamimidoyl-2-hydroxyphenyl)-propyl]-4-(1-oxy-pyridin-4-yl)-benzamideditrifluoroacetate;

N-[3-(5-Carbamimidoyl-2-hydroxyphenyl)-propyl]-4-(6-oxo-1,6-dihydropyridin-3-yl-benzamidetrifluroacetate;

N-[3-(5-Carbamimidoyl-2-hydroxyphenyl)-propyl]-4-(pyridazin-4-yl)benzamideditrifluoroacetate;

N-[3-(5-Carbamimidoyl-2-hydroxyphenyl)-propyl]-7-chlorobenzothiophene-2-carboxarnidetrifluroacetate;

(E)-N-[3-(5-Carbamimidoyl-2-hydroxy-phenyl)allyl]-4-(6-methoxy-pyridin-3-yl)-benzamidetrifluoroacetate;

(E)-N-[3-(5-Carbamimidoyl-2-hydroxy-phenyl)-allyl]-4-(6-oxo-1,6-dihydro-pyridin-3-yl)-benzamidetrifluoroacetate;

(E)-Biphenyl-4-carboxylic acid[3-(5-carbamimidoyl-2-hydroxy-phenyl)-allyl]-amide trifluoroacetate;

(E)-N-[3-(5-Carbamimidoyl-2-hydroxy-phenyl)-allyl]-4-pyridin-3-yl-benzamideditrifluoroacetate;

(E)-N-[3-(5-Carbamimidoyl-2-hydroxy-phenyl)-allyl]-4-pyridin-4-yl-benzamideditrifluoroacetate;

(E)-Biphenyl-3,4′-dicarboxylic acid 3-amide4′-{[3-(5-carbamiimidoyl-2-hydroxy-phenyl)-allyl]-amide}trifluoroacetate;

(E)-4-tert-Butyl-N-[3-(5-carbamimidoyl-2-hydroxy-phenyl)allyl]-benzamidetrifluoroacetate;

(E)-N-[3-(5-Carbamimidoyl-2-hydroxy-phenyl)-allyl]-4-(3H-imidazol-4-yl)-benzamideditrifluoroacetate;

(E)-Biphenyl-4,4′-dicarboxylic acid 4′-amide4-{[3-(5-carbamimidoyl-2-hydroxy-phenyl)-allyl]- amide}trifluoroacetate;

(E)-N-[3-(5-Carbamimidoyl-2-hydroxy-phenyl)-allyl]4-(1H-imidazol-2-yl)-benzamideditrifluoroacetate;

(E)-3-Oxo-2,3-dihydro-thieno[3,2-c]pyridazine-6-carboxylic acid[3-(5-carbamimidoyl-2-hydroxy-phenyl)-allyl]-amide trifluoroacetate;

(E)-5-Pyridin-2-yl-thiophene-2-carboxylic acid[3-(5-carbamimidoyl-2-hydroxy-phenyl)-allyl]-amide ditrifluoroacetate;

Biphenyl-4-carboxylic acid[3-(5-carbamimidoyl-2-hydroxy-phenyl)-propyl]-amide trifluoroacetate;

N-[3-(5-Carbamimidoyl-2-hydroxy-phenyl)-propyl]-4-(6-methoxy-pyridin-3-yl)-benzamidetrifluoroacetate;

Biphenyl-3,4′-dicarboxylic acid 3-amide4′-{[3-(5-carbamimidoyl-2-hydroxy-phenyl)-propyl]-amide}trifluoroacetate;

4-tert-Butyl-N-[3-(5-carbamimidoyl-2-hydroxy-phenyl)-propyl]-benzamidetrifluoroacetate;

[3-(5-Carbamimidoyl-2-hydroxy-phenyl)-propyl]-4-(3H-imidazol-4-yl)-benzamideditrifluoroacetate;

N-[3-(5-Carbamimidoyl-2-hydroxy-phenyl)-propyl]-4-(1H-imidazol-2-yl)-benzamideditrifluoroacetate;

5-Pyridin-2-yl-thiophene-2-carboxylic acid[3-(5-carbamimidoyl-2-hydroxy-phenyl)-allyl]-amide ditrifluoroacetate;and

N-[3-(5-Carbamimidoyl-2-hydroxy-phenyl)-propyl]-4-piperidin-4-yl-benzamideditrifluoroacetate.

More preferred species according to the invention are compounds 188,209-211, 213, 217, 231, 276-277, 280-281, 297, 300-301, 306, 310, 321,340, and 342.

It is to be understood that this invention covers all appropriatecombinations of the particular and preferred groupings referred toherein.

Compounds of Formula I may be prepared by the application or adaptationof known methods, by which is meant methods used heretofore or describedin the literature, or by methods according to this invention herein.

Scheme A exemplifies a general method for preparing intermediates foruse in preparing compounds of formula I according to the invention.

Scheme B exemplifies a general method for converting the intermediatesprepared according to Scheme A to compounds of formula I according tothe invention.

Scheme C exemplifies a general method for effecting interconversionsbetween compounds of formula I according to the invention.

In addition, the compounds of formula I wherein R₃ is hydroxymethy maybe converted to the corresponding thiomethyl compounds by treating thealcohol with an alkyl or aryl sulfonyl halide and displacing the alkylor aryl sulfonate with NaSH. the thiolmethyl compounds may then bealkylated or acylated to give other compounds within the scope of theinvention.

Scheme D exemplifies a general method for converting a nitrileintermediate to a compound of formula I and additional general methodsfor effecting interconversions between compounds of formula I accordingto the invention.

Scheme E exemplifies an additional general method for effectinginterconversions between compounds of formula I according to theinvention.

Scheme F exemplifies a general method for preparing compounds accordingto the present invention wherein R₄ of formula I is optionallysubstituted phenethyl.

Scheme G exemplifies a general method for preparing compounds accordingto the present invention wherein R₄ of formula I is methyl.

Scheme H exemplifies a general method for preparing compounds accordingto the present invention.

Scheme H exemplifies a general method for preparing compounds accordingto the present invention.

Scheme I exemplifies a general method for preparing compounds accordingto the present invention.

It will be apparent to those skilled in the art that certain compoundsof formula I can exhibit isomerism, for example geometrical isomerism,e.g., E or Z isomerism, and optical isomerism, e.g., R or Sconfigurations. Geometrical isomers include the cis and trans forms ofcompounds of the invention having alkenyl moieties. Individualgeometrical isomers and stereoisomers within formula I, and theirmixtures, are within the scope of the invention.

Such isomers can be separated from their mixtures, by the application oradaptation of known methods, for example chromatographic techniques andrecrystallization techniques, or they are separately prepared from theappropriate isomers of their intermediates, for example by theapplication or adaptation of methods described herein.

The compounds of the present invention are useful in the form of thefree base or acid or in the form of a pharmaceutically acceptable saltthereof. All forms are within the scope of the invention.

Where the compound of the present invention is substituted with a basicmoiety, acid addition salts are formed and are simply a more convenientform for use; and in practice, use of the salt form inherently amountsto use of the free base form. The acids which can be used to prepare theacid addition salts include preferably those which produce, whencombined with the free base, pharmaceutically acceptable salts, that is,salts whose anions are non-toxic to the patient in pharmaceutical dosesof the salts, so that the beneficial inhibitory effects on Factor Xainherent in the free base are not vitiated by side effects ascribable tothe anions. Although pharmaceutically acceptable salts of said basiccompounds are preferred, all acid addition salts are useful as sourcesof the free base form even if the particular salt, per se, is desiredonly as an intermediate product as, for example, when the salt is formedonly for purposes of purification, and identification, or when it isused as intermediate in preparing a pharmaceutically acceptable salt byion exchange procedures. Pharmaceutically acceptable salts within thescope of the invention are those derived from the following acids:mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acidand sulfamic acid; and organic acids such as acetic acid, citric acid,lactic acid, tartaric acid, malonic acid, methanesulfonic acid,ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,cyclohexylsulfamic acid, quinic acid, and the like. The correspondingacid addition salts comprise the following: hydrohalides, e.g.hydrochloride and hydrobromide, sulfate, phosphate, nitrate, sulfamate,acetate, citrate, lactate, tartarate, malonate, oxalate, salicylate,propionate, succinate, fumarate, maleate,methylene-bis-B-hydroxynaphthoates, gentisates, mesylates, isethionatesand di-p-toluoyltartratesmethanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate,respectively.

According to a further feature of the invention, acid addition salts ofthe compounds of this invention are prepared by reaction of the freebase with the appropriate acid, by the application or adaptation ofknown methods. For example, the acid addition salts of the compounds ofthis invention are prepared either by dissolving the free base inaqueous or aqueous-alcohol solution or other suitable solventscontaining the appropriate acid and isolating the salt by evaporatingthe solution, or by reacting the free base and acid in an organicsolvent, in which case the salt separates directly or can be obtained byconcentration of the solution.

The acid addition salts of the compounds of this invention can beregenerated from the salts by the application or adaptation of knownmethods. For example, parent compounds of the invention can beregenerated from their acid addition salts by treatment with an alkali,e.g. aqueous sodium bicarbonate solution or aqueous ammonia solution.

Where the compound of the invention is substituted with an acidicmoiety, base addition salts may be formed and are simply a moreconvenient form for use; and in practice, use of the salt forminherently amounts to use of the free acid form. The bases which can beused to prepare the base addition salts include preferably those whichproduce, when combined with the free acid, pharmaceutically acceptablesalts, that is, salts whose cations are non-toxic to the animal organismin pharmaceutical doses of the salts, so that the beneficial inhibitoryeffects on Factor Xa inherent in the free acid are not vitiated by sideeffects ascribable to the cations. Pharmaceutically acceptable salts,including for example alkali and alkaline earth metal salts, within thescope of the invention are those derived from the following bases:sodium hydride, sodium hydroxide, potassium hydroxide, calciumhydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide,zinc hydroxide, ammonia, ethylenediamine, N-methyl-glucamine, lysine,arginine, ornithine, choline, N,N′-dibenzylethylenediamine,chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine,diethylamine, piperazine, tris(hydroxymethyl)-aminomethane,tetramethylammonium hydroxide, and the like.

Metal salts of compounds of the present invention may be obtained bycontacting a hydride, hydroxide, carbonate or similar reactive compoundof the chosen metal in an aqueous or organic solvent with the free acidform of the compound. The aqueous solvent employed may be water or itmay be a mixture of water with an organic solvent, preferably an alcoholsuch as methanol or ethanol, a ketone such as acetone, an aliphaticether such as tetrahydrofuran, or an ester such as ethyl acetate. Suchreactions are normally conducted at ambient temperature but they may, ifdesired, be conducted with heating.

Amine salts of compounds of the present invention may be obtained bycontacting an amine in an aqueous or organic solvent with the free acidform of the compound. Suitable aqueous solvents include water andmixtures of water with alcohols such as methanol or ethanol, ethers suchas tetrahydrofuran, nitrites such as acetonitrile, or ketones such asacetone. Amino acid salts may be similarly prepared.

The base addition salts of the compounds of this invention can beregenerated from the salts by the application or adaptation of knownmethods. For example, parent compounds of the invention can beregenerated from their base addition salts by treatment with an acid,e.g. hydrochloric acid.

Pharmaceutically acceptable salts also include quaternary lower alkylammonium salts. The quaternary salts are prepared by the exhaustivealkylation of basic nitrogen atoms in compounds, including nonaromaticand aromatic basic nitrogen atoms, according to the invention, i.e.,alkylating the non-bonded pair of electrons of the nitrogen moietieswith an alkylating agent such as methylhalide, particularly methyliodide, or dimethyl sulfate. Quaternarization results in the nitrogenmoiety becoming positively charged and having a negative counter ionassociated therewith.

As will be self-evident to those skilled in the art, some of thecompounds of this invention do not form stable salts. However, acidaddition salts are most likely to be formed by compounds of thisinvention having a nitrogen-containing heteroaryl group and/or whereinthe compounds contain an amino group as a substituent. Preferable acidaddition salts of the compounds of the invention are those wherein thereis not an acid labile group.

As well as being useful in themselves as active compounds, salts ofcompounds of the invention are useful for the purposes of purificationof the compounds, for example by exploitation of the solubilitydifferences between the salts and the parent compounds, side productsand/or starting materials by techniques well known to those skilled inthe art.

The starting materials and intermediates are prepared by the applicationor adaptation of known methods, for example methods as described in theReference Examples or their obvious chemical equivalents, or by methodsaccording to this invention.

The present invention is further exemplified but not limited by thefollowing illustrative examples which illustrate the preparation of thecompounds according to the invention.

In the nuclear magnetic resonance spectra (NMR) the chemical shifts areexpressed in ppm relative to tetramethylsilane. Abbreviations have thefollowing significance: s=singlet; d=doublet; t=triplet; m=multiplet;dd=doublet of doublets; ddd=doublet of doublets of doublets; dt=doubletof triplets, b=broad.

EXAMPLE 1

To a stirred solution of 3-cyanobenzaldehyde (20 g; 153 mmol) in 100 mLof dry THF under N₂ at room temperature is added methyl(triphenylphosphoranylidene)acetate (61.2 g; 183 mmol). The mixture isallowed to stir overnight at room temperature and then concentrated invacuo. The crude residue is chromatographed (40% EtAc:Hexane) to give27.3 g (96%) of the acrylate 1. ¹H NMR (CDCl₃, δ): 7.43-7.8 (m, 5H),6.47 (d, J=12 Hz, 1H), 3.8 (s, 3H).

EXAMPLE 2

To a stirred solution of compound 1 (27.33 g) in 150 mL of EtOH is added2 g of 10% Pd/CaCO₃. The resulting mixture is hydrogenated under 45 PSIH₂ on a Parr shaker for 8 hours at room temperature. The mixture is thenfiltered through a plug of celite and the filtrate concentrated in vacuoto give 26.93 g (98%) of 2 as a clear oil.

¹H NMR (CDCl₃, d): 7.33-7.72 (m, 4H), 3.66 (s, 3H), 2.97 (t, J=7.8 Hz,2H), 2.62 (t, J=7.8 Hz, 2H).

EXAMPLE 3

To a stirred solution of compound 2 (16.8 g; 89 mmol) in 200 mL ofTHF:MeOH (2:1) at room temperature is added 9 mL of 10 N NaOH solutiondropwise. After 2h, most of the solvent is removed in vacuo and 30 mL of5N HCl is added. The resulting mixture is extracted several times withEtOAc. The combined extracts are dried (MgSO₄), filtered andconcentrated to give 9.8 g (63%) of pure acid 3 as a white solid. ¹H NMR(CDCl₃, δ): 7.35-7.55 (m, 4H), 2.98 (t, J=7.9 Hz, 2H), 2.7 (t, J=7.9 Hz,2H).

EXAMPLE 4

To a stirred solution of the carboxylic acid 3 (8.2 g; 47 mmol) and DMF(0.5 mL) in dry CH₂Cl₂ under N₂ at room temperature is added oxalylchloride (6.1 mL; 70 mmol) dropwise. After 1 hour, gas evolution ceasedand the solvent and excess oxalyl chloride is removed in vacuo. Theresidue is redissolved in 100 mL of dry CH₂Cl₂ and cooled to 0° C.Mercaptopyridine (5.6 g; 50 mmol) is added followed by triethylamine(7.9 mL; 56 mmol). The mixture is allowed to warm to r.t. and stirredfor 1 hour. The mixture is diluted with CH₂Cl₂ and washed with 1 N NaOH.The organic layer is dried (MgSO₄), filtered and concentrated. Theresidue is chromatographed (eluent=50% EtOAc:Hexane) to give 5.12 g(84%) of the thioester 4 as a yellow oil. ¹H NMR (CDCl₃, δ): 8.63 (d,J=9 Hz, 1H), 7.7-7.8 (m, 1H), 7.27-7.62 (m, 6H), 3.05 (s, 4H).

EXAMPLE 5

Magnesium sulfate (19.55 g; 162 mmol) is added to a stirred solution ofcinnamaldehyde (10.2 mL; 81 mmol) and p-anisidine (10 g; 81 mmol) in 200mL of CH₂Cl₂ under N₂ at 0° C. After 4 hours, the mixture is filteredand the filtrate concentrated to give 18.87 g (98%) of the iminecompound 5 as a gold:brown solid. ¹H NMR (CDCl₃, δ): 8.28 (m, 1H), 7.52(m, 2H), 7.38 (m, 3H), 7.2 (m, 2H), 7.12 (m, 2H), 6.93 (m, 2H), 3.82 (s,3H).

EXAMPLE 6

To a stirred solution of the thioester 5 (7 g; 26 mmol) in dry CH₂Cl₂(120 mL) under N₂ at −78° C. is added TiCl₄ solution (26.1 mL of 1 Msolution in CH₂Cl₂). After 15 minutes, triethylamine (3.6 mL; 26 mmol)is added dropwise. The resulting mixture is allowed to stir for ½ h at−78° C. and then a solution of imine 1 (4.42 g; 19 mmol in 20 mL CH₂Cl₂)is added dropwise. The mixture is then warmed to 0° C. After 1.5 hoursat this temperature, the mixture is quenched with saturated NaHCO₃solution and partitioned with water. The organic layer is washed with 1N NaOH, dried (MgSO₄) and concentrated in vacuo. The crude product ischromatographed (eluent=40% EtOAc:hexane) to give 2.42 g (32%) of a 5:1mixture of trans- /cis- b -lactam 6a and 6b as a gum. Major trans-Isomer6a: ¹H NMR (CDCl₃, δ): 7.2-7.6 (m, 11H), 6.8 (d, J=11 Hz, 2H), 6.65 (d,J=15.8 Hz, 1H), 6.2 (dd, J=15.8, 7.9 Hz, 1H), 4.32 (m, 1H), 3.72 (s,3H), 3.42 (m, 3H).

EXAMPLE 7

To a stirred solution of 6a, 6b (1.5 g; 3.8 mmol) in 60 mL of THF/CH₃CN(1/3) at −20° C. is added a solution of ceric ammonium nitrate (CAN,3.13 g; 5.7 mmol in 10 mL water). After 15 minutes, another 1.5 g of CANin 5 mL of water is added. After a further 30 minutes, the mixture isquenched with saturated NaHCO₃ solution and allowed to come to roomtemperature. The resulting suspension is filtered through a bed ofcelite, washing the celite pad several times with CH₂Cl₂ (total ca. 200mL). The filtrate layers are separated and the organic layer dried(MgSO₄), filtered and concentrated in vacuo. The crude product ischromatographed (eluent=60% EtOAc:hexane) to give 476 mg (43%) of puretrans-isomer 7a together with 85 mg of a mixture of cis-7b and trans-7aisomers.

Major trans-isomer 7a: ¹H NMR (CDCl₃, d): 7.17-7.65 (m, 9H), 6.52 (d,J=15.8 Hz, 1H), 6.25 (s, 1H), 6.14 (dd, J=15.8, 7.9 Hz, 1H), 3.97 (m,1H), 3-3.33 (m, 3H). Minor cis-isomer 7b: ¹H NMR (CDCl₃, d): 7.21-7.52(m, 9H), 6.62 (d, J=15.8 Hz, 1H), 6.45 (s, 1H), 6.1 (dd, J=15.8, 7.9 Hz,1H), 4.46 (m, 1H), 3.7 (m, 1H), 3.02-3.17 (m, 1H), 2.8-2.93 (m, 1H).

EXAMPLE 8

To a stirred solution of the trans-β-lactam 7a in dry CH₂Cl₂ under N₂ atr.t. is added triethylamine (4.04 mL; 29 mmol) dropwise.Biphenylcarbonyl chloride (5.05 g; 23.2 mmol) is then added followed byDMAP (50 mg). After 30 minutes the mixture is diluted with CH₂Cl₂ andwashed with 1 N HCl. The organic layer is then dried (Na₂SO₄), filteredand concentrated. The crude product is chromatographed (eluent=30%EtOAc:Hexane) gave 2.19 g (81%) of the product 8 as a solid. ¹H NMR(CDCl₃, δ): 8.06 (m, 2H), 7.2-7.75 (m, 16H), 6.67 (d, J=15.8, Hz, 1H),6.23 (dd, J=15.8, 7.9 Hz, 1H), 4.63 (m, 1H), 3.46 (m, 1H), 3.1-3.3 (m,2H).

EXAMPLE 9

To a stirred solution of the β-lactam 8 (2.19 g; 4.7 mmol) in 50 mL ofTHF at r.t. is added 1 N NaOH solution (13.6 mL) dropwise. After 2hours, most of the THF is removed in vacuo and 20 mL of 1 N HCl isadded. The resulting mixture is extracted with EtOAc. The extract isdried (Na₂SO₄), filtered and concentrated in vacuo. The crude product ispurified by RPHPLC (CH₃CN:water, 0.1% TFA, 40-100 gradient) and thefractions containing product are lyophilized to give 1.1 g (50%) ofcarboxylic acid 9 as a white solid. ¹H NMR (CDCl₃, δ): 7.18-7.97 (m,18H), 6.61 (d, J=15.8 Hz, 1H), 6.2 (dd, J=15.8, 7.9 Hz, 1H), 5.14 (m,1H), 3-3.22 (m, 3H).

EXAMPLE 10

To a stirred solution of the carboxylic acid 9 (105 mg; 0.22 mmol) in 3mL of dry MeOH at r.t. is added molecular sieves (ca. 50 mg). GaseousHCl is then bubbled in for ca. 2 minutes. The mixture is then allowed tostir over night at room temperature and then concentrated under a streamof N₂. A solution of NH₃ in MeOH (3 mL of 7 N solution) is then added tothe residue and the mixture refluxed for 1.5 hours, allowed to cool andthe solvent removed in vacuo. The residue is purified by RPHPLC(CH₃CN:water:0.1% TFA, 40-100 gradient) and the fractions containingproduct are lyophilized to give 73 mg (53%) of the product 10 as a whitesolid. ¹H NMR (DMSO-d₆, δ): 8.7 (d, J=8.6 Hz, 1H), 7.92 (d, J=9 Hz, 2H),7.78 (d, J=9 Hz, 2H), 7.75-7.21 (m, 14H), 6.67 (d, J=16.1 Hz, 1H), 6.4(dd, J=16.1, 7.8 Hz, 1H), 4.98 (dd, J=16.1, 7.8 Hz, 1H), 3.46 (s, 3H),3.25-3.18 (m, 1H), 3.05-2.88 (m, 2H).

EXAMPLE 11

This compound is prepared in a manner similar to compound 10 abovestarting from imine 5 and thioester 4. Benzoyl chloride is substitutedfor 4-biphenylcarbonyl chloride in the β-lactam acylation step. Thefinal product 11 is purified by reverse phase HPLC (CH₃CN:H₂O, 0.1% TFA)and lyophilized. ¹H NMR (MeOH-d₄, δ): 8.61 (d, J=11.3 Hz, 1H), 7.83 (d,J=7.5 Hz, 2H), 7.15-7.67 (m, 14H), 6.67 (d, J=15.8 Hz, 1H), 6.3 (dd,J=15.8, 7.9 Hz, 1H), 4.98 (m, 1H), 3.55 (s, 3H), 3.27 (m, 1H), 3.1 (m,2H).

EXAMPLE 12

This compound is prepared in a manner similar to compound 10 abovestarting from imine 5 and thioester 4. o-Toluoyl chloride is substitutedfor 4-biphenylcarbonyl chloride in the b-lactam acylation step. Thefinal product 12 is purified by reverse phase HPLC (CH₃CN:H₂O, 0.1% TFA)and lyophilized. ¹H NMR (DMSO-d₆, d): 9.3 (s, 1H), 9.15 (s, 1H), 8.7 (d,J=7.6 Hz, 1H), 7.7 (d, J=8 Hz, 2H), 7.6 (d, J=9 Hz, 2H), 7.2-7.6 (m,12H), 6.9 (d, J=8 Hz, 1H), 6.6 (d, J=15 Hz, 1H), 6.35 (dd, J=15, 6 Hz,1H), 4.9 (dd, J=15, 6 Hz, 1H), 3.55 (s, 3H), 3.2-3.3 (m, 1H), 2.8-3 (m,1H), 2.3 (s, 3H).

EXAMPLE 13

This compound is prepared in a manner similar to compound 10 abovestarting from imine 5 and thioester 4. m-Toluoyl chloride is substitutedfor 4-biphenylcarbonyl chloride in the β-lactam acylation step. Thefinal product 13 is purified by reverse phase HPLC (CH₃CN:H₂O, 0.1% TFA)and lyophilized. ¹H NMR (DMSO-d₆, d): 9.3 (s, 1 H), 9.2 (s, 1H), 8.7 (d,J=7.6 Hz, 1H), 7.7 (d, J=8 Hz, 2H), 7.6 (d, J=9 Hz, 2H), 7.2-7.6 (m,12H), 6.9 (d, J=8 Hz, 1H), 6.6 (d, J=15 Hz, 1H), 6.35 (dd, J=15, 6 Hz,1H), 4.9 (dd, J=16, 6 Hz, 1H), 3.6 (s, 3H), 3.2-3.3 (m, 1H), 2.8-3 (m,1H), 2.35 (s, 3H).

Other compounds prepared in a manner similar, using the appropriatestarting material, include the following:

EXAMPLE 14

This compound is prepared in a manner similar to compound 10 abovestarting from imine 5 and thioester 4. 4′-Ethyl-4-biphenylcarbonylchloride is substituted for 4-biphenylcarbonyl chloride in the β-lactamacylation step. The final product 14 is purified by reverse phase HPLC(CH₃CN:H₂O, 0.1% TFA) and lyophilized. ¹H NMR (DMSO-d₆, δ): 9.3 (s, 1H),9.15 (s, 1 H), 8.9 (d, J=7.6 Hz, 1H), 8.2 (d, J=8 Hz, 2H), 8 (d, J=9 Hz,2H), 7.4-7.9 (m, 12H), 7.2 (d, J=8 Hz, 1H), 6.9 (d, J=15 Hz, 1H), 6.6(dd, J=15, 6 Hz, 1H), 5.2 (dd, J=16, 6 Hz, 1H), 3.7 (s, 3H), 3.4-3.5 (m,1H), 3.1-3.2 (m, 1H), 2.85 (q, 2H), 1.4 (t, 3H).

EXAMPLE 15

This compound is prepared in a manner similar to compound 10 abovestarting from imine 5 and thioester 4.3′,4′-Dimethoxy-4-biphenylcarbonyl chloride is substituted for4-biphenylcarbonyl chloride in the β-lactam acylation step. The finalproduct 15 is purified by reverse phase HPLC (CH₃CN:H₂O, 0.1% TFA) andlyophilized. ¹H NMR (DMSO-d₆, d): 9.5 (s, 1H), 9.3 (s, 1H), 8.9 (d,J=7.6 Hz, 1H), 8.1 (d, J=8 Hz, 2H), 7.9 (d, J=9 Hz, 2H), 7.8 (s, 2H),7.4-7.7 (m, 11H), 7.25 (d, J=8 Hz, 1H), 6.6 (d, J=15 Hz, 1H), 6.4 (dd,J=15, 6 Hz, 1H), 4 (s, 3H), 3.9 (s, 3H), 3.7 (s, 3H), 3.4-3.5 (m, 1H),3.2-3.4 (m, 1H).

EXAMPLE 16

This compound is prepared in a manner similar to compound 10 abovestarting from imine 5 and thioester 4. 4-(2′-pyridyl)benzoyl chloride issubstituted for 4-biphenylcarbonyl chloride in the β-lactam acylationstep. The final product 16 is purified by reverse phase HPLC (CH₃CN:H₂O,0.1% TFA) and lyophilized. ¹H NMR (DMSO-d₆, δ): 9.5 (s, 1H), 9.3 (s,1H), 8.9 (d, J=7.6 Hz, 1H), 8.8 (s, 1H), 8.4 (d, J=8 Hz, 2H), 8.3 (d,J=9 Hz, 1H), 8.1 (d, J=8 Hz, 2H), 7.9 (s, 2H), 7.4-7.8 (m, 10H), 7.4 (d,J=8 Hz, 1H), 6.9 (d, J=15 Hz, 1H), 6.6 (dd, J=15, 6 Hz, 1H), 5.2 (dd,J=16, 6 Hz, 1H), 3.7 (s, 3H), 3.4-3.5 (m, 1H), 3.2-3.4 (m, 1H).

EXAMPLE 17

This compound is prepared in a manner similar to compound 10 abovestarting from imine 5 and thioester 4. 4-(3′-Pyridyl)benzoyl chloride issubstituted for 4-biphenylcarbonyl chloride in the β-lactam acylationstep. The final product 17 is purified by reverse phase HPLC (CH₃CN:H₂O,0.1% TFA) and lyophilized. ¹H NMR (DMSO-d₆, δ): 9.5 (s, 1H), 9.3 (s,1H), 8.9 (d, J=7.6 Hz, 1H), 8.5 (s, 1H), 8.5 (s, 1H), 8.2 (d, J=8 Hz,2H), 8.1 (d, J=9 Hz, 2H), 8 (d, J=8 Hz, 1H), 7.9 (s, 2H), 7.4-7.8 (m,9H), 7.4 (d, J=8 Hz, 1H), 6.9 (d, J=15 Hz, 1H), 6.6 (dd, J=15, 6 Hz,1H), 5.2 (dd, J=16, 6 Hz, 1H), 3.7 (s, 3H), 3.4-3.5 (m, 1H), 3.2-3.4 (m,1H).

EXAMPLE 18

This compound is prepared in a manner similar to compound 10 abovestarting from imine 5 and thioester 4. 4-(4′-Pyridyl)benzoyl chloride issubstituted for 4-biphenylcarbonyl chloride in the β-lactam acylationstep. The final product 18 is purified by reverse phase HPLC (CH₃CN:H₂O,0.1% TFA) and lyophilized. ¹H NMR (DMSO-d₆, δ): 9.5 (s, 1H), 9.3 (s,1H), 9 (d, J=7.6 Hz, 1H), 8.2 (s, 4H), 7.8 (s, 2H), 7.5-7.8 (m, 11H),7.4 (d, J=8 Hz, 1H), 6.9 (d, J=15 Hz, 1H), 6.6 (dd, J=15, 6 Hz, 1H), 5.2(dd, J=16, 6 Hz, 1H), 3.7 (s, 3H), 3.4-3.5 (m, 1H), 3.2-3.4 (m, 1H).

EXAMPLE 19

This compound is prepared in a manner similar to compound 10 abovestarting from imine 5 and thioester 4. 2′-Methyl-4-biphenylcarbonylchloride is substituted for 4-biphenylcarbonyl chloride in the β-lactamacylation step. The final product 19 is purified by reverse phase HPLC(CH₃CN:H₂O, 0.1% TFA) and lyophilized. ¹H NMR (DMSO-d₆, δ): 9.25 (s,1H), 9.03 (s, 1H), 8.71 (d, J=8.7 Hz, 1H), 7.86 (d, J=8 Hz, 2H), 7.61(d, J=8 Hz, 2H), 7.6-7.12 (m, 13H), 6.67 (d, J=15.9 Hz, 1H), 6.42 (dd,J=15.9, 7.8 Hz, 1H), 5.0 (dd, J=16, 7.9 Hz, 1H), 3.32 (s, 3H), 3.3-3.15(m, 1H), 3.11-2.9 (m, 2H), 2.21 (s, 3H).

EXAMPLE 20

This compound is prepared in a manner similar to compound 10 abovestarting from imine 5 and thioester 4. 3′-Methyl-4-biphenylcarbonylchloride is substituted for 4-biphenylcarbonyl chloride in the β-lactamacylation step. The final product 20 is purified by reverse phase HPLC(CH₃CN:H₂O, 0.1% TFA) and lyophilized. ¹H NMR (DMSO-d₆, δ): 9.25 (s,1H), 8.99 (s, 1H), 8.68 (d, J=8.7 Hz, 1H), 7.9 (d, J=9 Hz, 1H), 7.75 (d,J=9 Hz, 1H), 7.68-7.15 (m, 13H), 6.68 (d, J=15.9 Hz, 1H), 6.4 (dd,J=15.9, 7.8 Hz, 1H), 5.0 (dd, J=16, 7.9 Hz, 1H), 3.46 (s, 3H), 3.28-3.18(m, 1H), 3.1-2.9 (m, 2H), 2.36 (S, 3H).

EXAMPLE 21

This compound is prepared in a manner similar to compound 10 abovestarting from imine 5 and thioester 4. 2′-Methoxy-4-biphenylcarbonylchloride is substituted for 4-biphenylcarbonyl chloride in the β-lactamacylation step. The final product 21 is purified by reverse phase HPLC(CH₃CN:H₂O, 0.1% TFA) and lyophilized. ¹H NMR (DMSO-d₆, δ): 9.25 (s,1H), 9.03 (s, 1H), 8.76 (δ, J=8.7 Hz, 1H), 7.83 (d, J=9.5 Hz, 2H),7.65-6.95 (m, 15H), 6.64 (d, J=15.9 Hz, 1H), 6.4 (dd, J=15.9, 7.8 Hz,1H), 4.99 (dd, J=16, 7.9 Hz, 1H), 3.75 (s, 3H), 3.46 (s, 3H), 3.3-3.17(m, 1H), 3.1-2.9 (m, 2H).

EXAMPLE 22

This compound is prepared in a manner similar to compound 10 abovestarting from imine 5 and thioester 4. 3′-Methoxy-4-biphenylcarbonylchloride is substituted for 4-biphenylcarbonyl chloride in the β-lactamacylation step. The final product 22 is purified by reverse phase HPLC(CH₃CN:H₂O, 0.1% TFA) and lyophilized. ¹H NMR (DMSO-d₆, δ): 9.23 (s,1H), 8.96 (s, 1H), 8.69 (d, J=8.7 Hz, 1H), 7.9 (d, J=9.6 Hz, 2H),7.68-7.18 (m, 12H), 6.96 (dd, J=9.6, 2 Hz, 1H), 6.64 (d, J=15.9 Hz, 1H),6.39 (dd, J=15.9, 7.8 Hz, 1H), 4.98 (dd, J=16, 7.9 Hz, 1H), 3.81 (s,3H), 3.47 (s, 3H), 3.28-3.17 (m, 1H), 3.08-2.86 (m, 2H).

EXAMPLE 23

This compound is prepared in a manner similar to compound 10 abovestarting from imine 5 and thioester 4. 2-Naphthylcarbonyl chloride issubstituted for 4biphenylcarbonyl chloride in the β-lactam acylationstep. The final product 23 is purified by reverse phase HPLC (CH₃CN:H₂O,0.1% TFA) and lyophilized. ¹H NMR (DMSO-d₆, δ): 9.24 (s, 1H), 9.02 (s,1H), 8.83 (d, J=8.6 Hz, 1H), 8.4 (s, 1H), 8.08-7.85 (m, 4H), 7.68-7.2(m, 12H), 6.68 (d, J=15.8 Hz, 1H), 6.43 (dd, J=15.8, 7.8 Hz, 1H), 5.03(dd, J=15.8, 7.8 Hz, 1H), 3.46 (s, 3H), 3.28-3.2 (m, 1H), 3.13-2.95 (m,2H).

EXAMPLE 24

This compound is prepared in a manner similar to compound 10 abovestarting from imine 5 and thioester 4. 1-Naphthylcarbonyl chloride issubstituted for 4-biphenylcarbonyl chloride in the β-lactam acylationstep. The final product 24 is purified by reverse phase HPLC (CH₃CN:H₂O,0.1% TFA) and lyophilized. ¹H NMR (DMSO-d₆, δ): 9.27 (s, 1H), 9.11 (s,1H), 8.88 (d, J=8.67 Hz, 1H), 8.18-8.07 lyophilized. ¹H NMR (DMSO-d₆,δ): 9.27 (s, 1H), 9.11 (s, 1H), 8.88 (d, J=8.67 Hz, 1H), 8.18-8.07 (m,1H), 8.05-7.9 (m, 2H), 7.7-7.2 (m, 13H), 6.73 (d, J=15.9 Hz, 1H), 6.4(dd, J=15.9, 7.8 Hz, 1H), 5.07 (dd, J=16, 7.9 Hz, 1H), 3.52 (s, 3H),3.28-3.17 (m, 1H), 3.12-2.95 (m, 2H).

EXAMPLE 25

This compound is prepared in a manner similar to compound 10 abovestarting from imine 5 and thioester 4. 3′-Ethyl-4-biphenylcarbonylchloride is substituted for 4-biphenylcarbonyl chloride in the β-lactamacylation step. The final product 25 is purified by reverse phase HPLC(CH₃CN:H₂O, 0.1% TFA) and lyophilized. ¹H NMR (DMSO-d₆, δ): 9.25 (s,1H), 9.05 (s, 1H), 8.68 (d, J=8.6 Hz, 1H), 7.88 (d, J=9 Hz, 2H), 7.76(d, J=9 Hz, 2H), 7.62 (m, 2H), 7.55-7.15 (m, 11H), 6.66 (d, J=16 Hz,1H), 6.4 (dd, J=16, 7.8 Hz, 1H), 4.96 (dd, J=16, 7.8 Hz, 1H), 3.47 (s,3H), 3.3-3.18 (m, 1H), 3.1-2.88 (m, 2H), 2.67 (q, J=8.5 Hz, 2H), 1.22(t, J=8.5 Hz, 3H).

EXAMPLE 26

This compound is prepared in a manner similar to compound 10 abovestarting from imine 5 and thioester 4. 4′-Methoxy-4-biphenylcarbonylchloride is substituted for 4-biphenylcarbonyl chloride in the β-lactamacylation step. The final product 26 is purified by reverse phase HPLC(CH₃CN:H₂O, 0.1% TFA) and lyophilized. ¹H NMR (DMSO-d₆, δ): 9.23 (s,1H), 8.96 (s, 1H), 8.66 (d, J=8.7 Hz, 1H), 7.88 (d, J=9.1 Hz, 2H),7.72-7.22 (m, 11H), 7.03 (d, J=8.7 Hz, 2H), 6.64 (d, J=16.1 Hz, 1H), 6.4(dd, J=16.1, 7.9 Hz, 1H), 4.97 (dd, J=16.1, 7.9 Hz, 1H), 3.77 (s, 3H),3.46 (s, 3H), 3.28-3.15 (m, 1H), 3.08-2.88 (m, 2H).

EXAMPLE 27

This compound is prepared in a manner similar to compound 10 abovestarting from imine 5 and thioester 4. 2′, 4′-Dimethoxy-4biphenylcarbonyl chloride is substituted for4-biphenylcarbonyl chloride in the β-lactam acylation step. The finalproduct 27 is purified by reverse phase HPLC (CH₃CN:H₂O, 0.1% TFA) andlyophilized. ¹H NMR (DMSO-d₆, δ): 9.23 (s, 1H), 9.07 (s, 1H), 8.63 (d,J=9 Hz, 1H), 7.81 (d, J=8.9 Hz, 2H), 7.68-7.15 (m, 14H), 6.72-6.52 (m,1H), 6.45-6.3 (m, 1H), 5.04-4.9 (m, 1H), 3.78 (s, 3H), 3.75 (s, 3H),3.51 (s, 3H), 3.21-3.15 (m, 1H), 3.08-2.85 (m, 2H).

EXAMPLE 28

This compound is prepared in a manner similar to compound 10 abovestarting from imine 5 and thioester 4. 2′-Ethyl-4-biphenylcarbonylchloride is substituted for 4-biphenylcarbonyl chloride in the β-lactamacylation step. The final product 28 is purified by reverse phase HPLC(CH₃CN:H₂O, 0.1% TFA) and lyophilized. ¹H NMR (DMSO-d₆, δ): 9.25 (s,1H), 8.92 (s, 1H), 8.69 (d, J=8.7 Hz, 1H), 7.78 (d, J=9 Hz, 2H),7.68-7.08 (m, 15H), 6.65 (d, J=15.9 Hz, 1H), 6.38 (dd, J=15.9, 7.8 Hz,1H), 5.0 (dd, J=16, 7.9 Hz, 1H), 3.46 (s, 3H), 3.28-3.18 (m, 1H), 2.52(q, J=9.6 Hz, 2H), 0.98 (t, J=9.6 Hz, 3H).

EXAMPLE 29

This compound is prepared in a manner similar to compound 10 abovestarting from imine 5 and thioester 4. 4′-Methyl-4-biphenylcarbonylchloride is substituted for 4-biphenylcarbonyl chloride in the β-lactamacylation step. The final product 29 is purified by reverse phase HPLC(CH₃CN:H₂O, 0.1% TFA) and lyophilized. ¹H NMR (DMSO-d₆, δ): 9.22 (s,1H), 8.91 (s, 1H), 8.68 (d, J=8.7 Hz, 1H), 7.85 (d, J=9 Hz, 2H), 7.75(d, J=9 Hz, 2H), 7.65-7.2 (m, 13H), 6.65 (d, J=15.9 Hz, 1H), 6.39 (dd,J=15.9, 7.8 Hz, 1H), 4.99 (dd, J=16, 7.9 Hz, 1H), 3.46 (s, 3H),3.28-3.18 (m, 1H), 3.08-288 (m, 2H), 2.35 (s, 3H).

EXAMPLE 30

This compound is prepared in a manner similar to compound 10 abovestarting from imine 5 and thioester 4. 3′-Ethoxy-4-biphenylcarbonylchloride is substituted for 4-biphenylcarbonyl chloride in the β-lactamacylation step. The final product 30 is purified by reverse phase HPLC(CH₃CN:H₂O, 0.1% TFA) and lyophilized. ¹H NMR (DMSO-d₆, δ): 9.22 (s,1H), 9.05 (s, 1H), 8.7 (d, J=8.7 Hz, 1H), 7.88 (d, J=9 Hz, 2H), 7.76 (d,J=9 Hz, 2H), 7.68-7.12 (m, 12H), 6.98-6.85 (m, 1H), 6.67 (d, J=16 Hz,1H), 6.4 (dd, J=16, 7.8 Hz, 1H), 5.01 (dd, J=16, 7.8 Hz, 1H), 4.08 (q,J=7.5 Hz, 2H), 3.45 (s, 3H), 3.25-3.15 (m, 1H), 3.08-2.89 (m, 2H), 1.32(t, J=7.5 Hz, 2H).

EXAMPLE 31

This compound is prepared in a manner similar to compound 10 abovestarting from imine 5 and thioester 4. 4′-Ethoxy-4-biphenylcarbonylchloride is substituted for 4-biphenylcarbonyl chloride in the β-lactamacylation step. The final product 31 is purified by reverse phase HPLC(CH₃CN:H₂O, 0.1% TFA) and lyophilized. ¹H NMR (DMSO-d₆, δ): 9.26 (s,1H), 9.02 (s, 1H), 8.64 (d, J=8.7 Hz, 1H), 7.86 (d, J=9 Hz, 2H), 7.72(d, J=9 Hz, 2H), 7.7-7.22 (m, 11H), 7.01 (m, 10.4 Hz, 2H), 6.64 (d,J=15.9 Hz, 1H), 6.38 (dd, J=15.9, 7.8 Hz, 1H), 4.98 (dd, J=16, 7.8 Hz,1H), 4.06 (q, J=8.2 Hz, 2H), 3.45 (s, 3H), 3.3-3.18 (m, 1H), 3.08-2.85(m, 1H), 1.32 (t, J=8.2 Hz, 3H).

EXAMPLE 32

This compound is prepared in a manner similar to compound 10 abovestarting from imine 5 and thioester 4. 2′-Ethoxy-4-biphenylcarbonylchloride is substituted for 4-biphenylcarbonyl chloride in the β-lactamacylation step. The final product 32 is purified by reverse phase HPLC(CH₃CN:H₂O, 0.1% TFA) and lyophilized. ¹H NMR (DMSO-d₆, δ): 9.24 (s,1H), 9.11 (s, 1H), 8.68 (d, J=8.7 Hz, 1H), 7.85 (d, J=9 Hz, 1H), 7.6 (d,J=9 Hz, 2H), 7.59-6.95 (m, 13H), 6.65 (d, J=1H), 6.39 (dd, J=15.9, 7.8Hz, 1H), 4.98 (dd, J=16, 7.8 Hz, 1H), 4.03 (q, J=8.1 Hz, 2H), 3.47 (s,3H), 3.28-3.18 (m, 1H), 3.1-2.88 (m, 2H), 1.24 (t, J=8.1 Hz, 3H).

EXAMPLE 33

To a stirred solution of 2-Naphthaldehyde (20 g; 0.13 mol) in 200 mL ofCH₂Cl₂ at room temp. is added p-anisidine (15.8 g; 0.13 mol) followed byanhydrous magnesium sulfate (16.9 g; 0.14 mol). After 3.5 hours, themixture is filtered and the filtrate concentrated in vacuo to give 31.5g (92%) of the imine 33. ¹H NMR (CDCl₃, δ): 8.64 (s, 1H), 8.19 (m, 2H),7.78-7.98 (m, 3H), 7.43-7.56 (m, 2H), 7.32 (m, 2H), 6.96 (m, 2H), 3.83(s, 3H).

EXAMPLE 34

Prepared using trans-3-(2′-naphthyl)acrolein, p-anisidine and anhydrousmagnesium sulfate as described for compound 33 above. ¹H NMR (CDCl₃, δ):8.35 (d, J=9 Hz, 1H), 7.78-7.9 (m, 4H), 7.72 (m, 1H), 7.5 (m, 2H), 7.25(m, 4H), 6.93 (m, 2H), 3.82 (s, 3H).

EXAMPLE 35

Prepared using trans-3-(4′-biphenyl)acrolein, p-anisidine and anhydrousmagnesium sulfate as described for compound 33 above. ¹H NMR (CDCl₃, δ):8.33 (d, J=9 Hz, 1H), 7.2-7.68 (m, 13H), 6.9 (m, 2H), 3.82 (s, 3H).

EXAMPLE 36

Prepared using 4-biphenylcarboxaldehyde, p-anisidine and anhydrousmagnesium sulfate as described for compound 33 above. ¹H NMR (CDCl₃, δ):8.52 (s, 1H), 7.97 (m, 2H), 7.62-7.73 (m, 4H), 7.35-7.52 (m, 3H), 7.27(m, 2H), 6.95 (m, 2H), 3.85 (s, 3H).

EXAMPLE 37

This compound is prepared in a manner similar to compound 10 startingfrom imine 33 and thioester 4. Benzoyl chloride is substituted for4-biphenylcarbonyl chloride in the β-lactam acylation step. The finalproduct 37 is purified by reverse phase HPLC (CH₃CN:H₂O, 0.1% TFA) andlyophilized. ¹H NMR (MeOH-d₄, δ): 9.01 (d, J=9.4 Hz, 1H), 7.77-7.98 (m,6H), 7.43-7.67 (m, 9H), 5.53 (m, 1H), 3.56 (m, 1H), 3.54 (s, 3H), 3.1(m, 1H), 2.81 (m, 1H).

EXAMPLE 38

This compound is prepared in a manner similar to compound 10 startingfrom imine 34 and thioester 4. Benzoyl chloride is substituted for4-biphenylcarbonyl chloride in the β-lactam acylation step. The finalproduct 38 is purified by reverse phase HPLC (CH₃CN:H₂O, 0.1% TFA) andlyophilized. ¹H NMR (DMSO-d₆, δ): 9.27 (s, 2H), 9.1 (s, 2H), 8.72 (d,1H), 7.4-7.95 (m, 16 H), 6.86 (d, J=18 Hz), 1H), 6.54 (dd, J=10, 6 Hz,1H), 5.03 (m, 1H), 3.48 (s, 3H), 3.32 (m, 1H), 3.04 (m, 2H).

EXAMPLE 39

This compound is prepared in a manner similar to compound 10 startingfrom imine 35 and thioester 4. Benzoyl chloride is substituted for4-biphenylcarbonyl chloride in the β-lactam acylation step. The finalproduct 39 is purified by reverse phase HPLC (CH₃CN:H₂O, 0.1% TFA) andlyophilized. ¹H NMR (DMSO-d₆, δ): 9.25 (s, 2H), 9.11 (s, 2H), 8.74 (d,1H), 7.30-8 (m, 22H), 6.23 (d, J=18 Hz, 1H), 6.47 (dd, J=18, 6 Hz, 1H),5.04 (m, 1H), 3.49 (s, 3H), 3.3 (m, 1H), 3.03 (m, 2H).

EXAMPLE 40

This compound is prepared in a manner similar to compound 10 startingfrom imine 36 and thioester 4. Benzoyl chloride is substituted for4-biphenylcarbonyl chloride in the β-lactam acylation step. The finalproduct 40 is purified by reverse phase HPLC (CH₃CN:H₂O, 0.1% TFA) andlyophilized. ¹H NMR (DMSO-d₆, δ): 9.23 (s, 2H), 9.05 (s, 2H), 8.97 (s,2H), 7.28-7.8 (m, 18H), 5.35 (t, 1H), 3.42 (s, 3H), 3.31 (m, 1H), 2.89(dd, 1H), 2.6 (dd, 1H).

EXAMPLE 41

To a stirring solution of the carboxylic acid 9 (980 mg; 2 mmol) andtriethylamine (0.44 mL; 3.2 mmol) in dry THF under N₂ at 0° C. is addedi-butylchloroformate (0.39 mL; 3 mmol) dropwise. After mixture isallowed to warm up to room temperature. After 1 hour, most of the THF isremoved in vacuo. Water is then added and the mixture extracted withethyl acetate. The combined extracts are dried (MgSO₄), filtered andconcentrated. The crude product is purified by chromatography(eluent=35% EtOAc:Hexane) to give 720 mg (76%) of the alcohol 41. ¹H NMR(CDCl₃, δ): 7.92 (d, J=9 Hz, 2H), 7.2-7.72 (m, 16H), 6.67 (d, J=15.5 Hz,1H), 6.27 (dd, J=15.5, 7.8 Hz, 1H), 4.94 (m, 1H), 3.88 (m, 1H), 3.5 (m,1H), 3.12 (m, 1H), 2.82-3.03 (m, 2H), 1.95 (m, 1H).

EXAMPLE 42

To a stirred solution of the alcohol 41 (106 mg; 0.22 mmol) in 3 mL ofdry MeOH at r.t. is added molecular sieves (ca. 50 mg). Gaseous HCl isthen bubbled in for ca. 2 minutes. The mixture is then allowed to stirover night at room temperature and then concentrated under a stream ofN₂. A solution of NH₃ in MeOH (3 mL of 7 N solution) is then added tothe residue and the mixture refluxed for 1.5 hour, allowed to cool andthe solvent removed in vacuo. The residue is purified by RPHPLC (CH₃CN:water: 0.1% TFA, 40-100 gradient) and the fractions containing productare lyophilized to give 29 mg (22%) of the product 42 as thetrifluoroacetate salt.

EXAMPLE 43

To a stirring solution of the alcohol compound (88 mg; 0.2 mmol) in 2 mLof 2:1 THF:DMF under N₂ at 0° C. is added NaH (15 mg of 60% dispersion;0.4 mmol). After 15 minutes, methyl iodide (0.02 mL; 0.3 mmol) is addedand the mixture allowed to warm to room temperature. After 2 hours, themixture is quenched with saturated NaHCO₃ solution. Most of the THF isremoved in vacuo and the residue diluted with water and extracted withCH₂Cl₂. The combined extracts are dried (Na₂SO₄), filtered andconcentrated. The crude product is chromatographed (eluent=35%EtOAc:Hexane) to give 21 mg (23%) of the product 43 together with 34 mgof recovered alcohol 41. ¹H NMR (CDCl₃, δ):7.93 (d, J=9.3 Hz, 2H),7.15-7.83 (m, 16H), 6.57 (d, J=15.8 Hz, 1H), 6.22 (dd, J=15.8, 6.8 Hz,1H), 5 (m, 1H), 3.75 (m, 1H), 3.42 (s, 3H), 3.27 (m, 1H), 2.87-3.03 (m,2H), 2.12 (m, 1H).

EXAMPLE 44

Into a stirring solution of compound 43 (20 mg; 0.04 mmol) in 1.5 mL of2:1 pyridine:Et₃N is bubbled H₂S for about 1 minute. The mixture isallowed to stir overnight at room temperature and then concentratedunder a stream of N₂ and then taken up into 2 mL of CH₂Cl₂. Methyliodide (1 mL) is added and the mixture refluxed for 1 hour. The solventis then removed in vacuo, the residue taken up into 2 mL of MeOH andNH₄OAc (30 mg) is added. The resulting mixture is refluxed for 1 hourand then allowed to cool. The solvent is then removed in vacuo and theresidue is purified by RPHPLC (CH₃CN:H₂O, 0.1% TFA, 40 to 100% CH₃CNgradient ) and the fractions containing product are lyophilized to give13 mg (51%) of product 44 as the trifluoroacetate salt. ¹H NMR (MeOH-d₄,δ): 8.47 (d, J=7.9 Hz, 1H), 7.95 (d, J=8 Hz, 2H), 7.78 (d, J=8 Hz, 2H),7.17-7.73 (m, 14H), 6.55 (d, J=15.8 Hz, 1H), 6.31 (dd, J=15.8,7.9 Hz,1H), 4.77 (m, 1H), 3.7 (dd, J=9.5,3.1 Hz, 1H), 3.47 (dd, J=9.5, 3.1 Hz,1H), 3 (d, J=7.9 Hz, 2H), 2.35 (m, 1H).

EXAMPLE 45

A mixture of alcohol 41 (480 mg; 1 mmol), pyridine (0.40 mL; 4.9 mmol)and acetic anhydride (0.12 mL; 1.2 mmol) is stirred overnight at roomtemperature. The next day, 3 drops of pyridine and acetic anhydride areadded. The next day, the reaction is not complete and so 4 mg of DMAP isadded. After 1 hour, the reaction is complete by tlc. The mixture isdiluted with CH₂Cl₂ and washed with 0.1 N HCl solution. The organiclayer is dried (MgSO₄), filtered and concentrated to give 520 mg of 45.¹H NMR (CDCl₃, δ): 7.98 (d, J=8 Hz, 2H), 7.73 (d, J=8 Hz, 2H), 7.67 (d,J=8 Hz, 2H), 7.17-7.58 (m, 12H), 6.94 (d, 1H), 6.55 (d, J=18 Hz, 1H),6.21 (dd, J=18, 5 Hz, 1H), 5.1 (m, 1H), 4.38 (m, 1H), 4.08 (m, 1H),2.68-2.97 (m, 2H), 2.51 (m, 1H).

EXAMPLE 46

Compound 45 is converted to the corresponding amidine 46 using thehydrogen sulfide /methyl iodide: ammonium acetate sequence described forthe conversion of 43 to 44. The producr 46 is purified by RPHPLC andisolated as its trifluoroacetate salt. ¹H NMR (DMSO-d₆, δ): 9.31 (s,2H), 8.97 (s, 2H), 8.7 (d, 1H), 7.18-8 (m, 18H), 6.6 (d, J=18 Hz, 1H),6.40 (dd, J=18, 6 Hz, 1H), 4.83 (m, 1H), 4.02 (m, 1H), 3.84 (m, 2H),2.95 (m, 1H), 2.57 (m, 1H), 1.93 (s, 3H).

EXAMPLE 47

Carboxylic acid 9 is converted to its corresponding amidine 47 using thehydrogen sulfide: methyl iodide: ammonium acetate sequence described forthe conversion of 43 to 44. The produce 47 is isolated by RPHPLC as itstrifluoroacetate salt. ¹H NMR (MeOH-d₄, δ): 8 (d, J=9 Hz, 2H), 7.82 (d,J=9 Hz, 2H), 7.22-7.77 (m, 14H), 6.73 (d, J=15.8 Hz, 1H), 6.4 (dd,J=15.8, 7.9 Hz, 1H), 4.95 (m, 1H), 3.08-3.45 (m, 3H).

EXAMPLE 49

To a stirring solution of the carboxylic acid 48 (120 mg; 0.29 mmol) in5 mL of dry CH₂Cl₂ under N₂ at room temperature is added triethylamine(0.05 mL; 0.38 mmol). iso-propyl chloroformate (0.38 mL of 1 M solutionin toluene) is added dropwise. After 30 minutes, DMAP (18 mg; 0.15 mmol)is added and the mixture allowed to further stir for 1.5 hours at roomtemperature. The mixture is then diluted with CH₂Cl₂ and washed with 1 NHCl. The organic layer is then dried (MgSO₄), filtered and concentrated.The crude product is chromatographed (eluent=40% EtOAc:Hexane to give 44mg (33 %) of the corresponding isopropyl ester. This compound is thenconverted to the corresponding amidine 49 via the hydrogen sulfide:methyl iodide: ammonium acetate procedure as described for theconversion of 43 to 44. The product 49 is purified by RPHPLC andisolated as its trifluoroacetate salt. ¹H NMR (MeOH-d₄, δ): 8.6 (d,J=7.9 Hz, 1H), 7.85 (d, J=8 Hz, 2H), 7.16-7.7 (m, 12H), 6.69 (d, J=15.8Hz, 1H), 6.32 (dd, J=15.8, 7.9 Hz, 1H), 4.98 (m, 1H), 4.85 (m, 1H), 3.23(m, 1H), 3.08 (m, 2H), 1.07 (s, J=6 Hz, 3H), 0.97 (d, J=6 Hz, 3H).

EXAMPLE 50

This compound is prepared by conversion of 48 to the correspondingamidine using the hydrogen sulfide: methyl iodide: ammonium acetatesequence described for the conversion of 43 to 44. The product 50 ispurified by RPHPLC and isolated as its trifluoroacetate salt. ¹H NMR(MeOH-d₄, δ): 8.6 (d, J=7.9 Hz, 1H), 7.85 (d, J=8 Hz, 2H), 7.16-7.7 (m,12H), 6.69 (d, J=15.8 Hz, 1H), 6.32 (dd, J=15.8, 7.9 Hz, 1H), 4.98 (m,1H), 4.85 (m, 1H), 3.23 (m, 1H), 3.08 (m, 2H), 1.07 (d, J=6 Hz, 3H),0.97 (d, J=6 Hz, 3H).

EXAMPLE 51

Into a stirred solution of the carboxylic acid 50 (96 mg; 0.18 mmol) in3 mL of EtOH at room temperature is bubbled HCl for ca. 3 minutes. Themixture is allowed to stir for 7 hours at room temperature and thenstored in the refrigerator (0° C.) over the weekend. The solvent is thenremoved in vacuo and the residue purified by RPHPLC. The product 51 isisolated as its trifluoroacetate salt. ¹H NMR (MeOH-d₄, δ): 8.63 (d,J=7.9 Hz, 1H), 7.84 (d, J=8 Hz, 2H), 7.16-7.68 (m, 12H), 6.68 (d, J=15.8Hz, 1H), 6.32 (dd, J=15.8, 7.9 Hz, 1H), 5 (m, 1H), 4.02 (q, 2H), 3.25(m, 1H), 3.07 (d, J=7.9 Hz, 2H), 1.05 (t, 3H).

EXAMPLE 52

A mixture of compound 11 and 10% Pd/C (25 mg) in EtOAc (2 mL): EtOH (5mL) is hydrogenated under 45 PS1H₂ for 19 hours at room temperature. Themixture is then filtered through a bed of celite and the filtrateconcentrated. The crude product is purified by RPHPLC (CH₃CN:water: 0.1%TFA, 10-100% CH₃CN gradient) and the fractions containing product arelyophilized to give 21 mg of 52. ¹H NMR (MeOH-d₄, δ): 8.27 (d, J=9.3 Hz,1H), 7.83 (m, 2H), 7.43-7.65 (m, 7H), 7.09-7.27 (m, 5H), 4.35 (m, 1H),3.58 (s, 3H), 2.95-3.15 (m, 3H), 2.54-2.75 (m, 2H), 1.93 (m, 2H).

Resolution of Compound 10

Racemic compound 10 (ca. 650 mg, single diastereomer with the presumedsyn-stereochemistry shown) is resolved into its two enantiomers 53 (lateeluting isomer) and 54 (early eluting isomer) using preparative HPLC(Chiralpak AD column, 50 mm ID×500 mm, 15 microns). The mobile phase isheptane (A) with 0.1% TFA and i-propanol (B) with 0.1% TFA, isocratic20% A, 80% B (Flow=200 mL: minute). The late eluting isomer is isolatedby concentration in vacuo. The yield is 180 mg. The %ee enantiomer 53 isfound to be 100% by analytical HPLC (Chiralpak AD). The ¹H NMR spectrafor 53 and 54 are identical. ¹H NMR (DMSO-d₆, δ): 8.7 (d, J=8.6 Hz, 1H),7.92 (d, J=9 Hz, 2H), 7.78 (d, J=9 Hz, 2H), 7.75-7.21 (m, 14H), 6.67 (d,J=16.1 Hz, 1H), 6.4 (dd, J=16.1, 7.8 Hz, 1H), 4.98 (dd, J=16.1, 7.8 Hz,1H), 3.46 (s, 3H), 3.25-3.18 (m, 1H), 3.05-2.88 (m, 2H).

EXAMPLE 55

The hydrogenation of compound 53 (late eluting enantiomer) is carriedout as for compound 52 above except ethyl acetate is omitted. Theproduct is purified by RPHPLC (CH₃CN:water: 0.1% TFA, 40-100% CH₃CN) andthe product 55 is isolated as the trifluoroacetate salt. ¹H NMR(MeOH-d₄, δ): 8.3 (d, J=9.3 Hz, 1H), 7.84 (m, 2H), 7.07-7.8 (m, 16H),4.37 (m, 1H), 3.6 (s, 3H), 2.97-3.17 (m, 3H), 2.57-2.77 (m, 2H), 1.95(m, 2H).

EXAMPLE 56

To a solution of N-a-Boc-D-Phenylalanine (38 mmol) in 80 mL of drytetrahydrofuran is added N-methyl morpholine (38 mmol) in a singleportion, followed by isobutyl chloroformate (38 mmol) in a similarfashion, at −20° C. The reaction mixture is stirred for 10 minutes at−20° C. and filtered into a preformed ethereal solution of diazomethane(˜70 mmol) at 0° C. The resulting solution is allowed to stand at 0° C.for 20 minutes. Excess diazomethane is decomposed by the dropwiseaddition of glacial acetic acid and solvents are removed in vacuo. Theresulting oil is dissolved in 150 mL of dry methanol. A solution ofsilver benzoate (8 mmol) in 17 mL of triethylamine is slowly added withstirring, at room temperature. The resulting black reaction mixture isstirred for 45 minutes at room temperature. Methanol is removed in vacuoand the residue taken up in 700 mL of ethyl acetate. The mixture isfiltered through celite and washed sequentially with saturated sodiumbicarbonate (3×150 mL), water (1×150 mL), 1N potassium bisulfate (3×150mL) and brine (1×150 mL). The organic layer is dried over magnesiumsulfate, filtered, concentrated in vacuo, and purified by flashchromatography (3:1 hexanes:ethyl acetate).

EXAMPLE 57

Compound 57 is prepared using the procedure described for Compound 56,substituting N-a-Boc-D-alanine.

EXAMPLE 58

Compound 58 is prepared using the procedure described for Compound 56,substituting N-a-Boc-D-homophenylalanine.

EXAMPLE 59

Compound 59 is prepared using the procedure described for Compound 56,substituting N-a-Boc-D-3-pyridylalanine.

EXAMPLE 60

Compound 60 is prepared using the procedure described for 56,substituting N-a-Boc-D-isoleucine.

EXAMPLE 61

Compound 61 is prepared using the procedure described for Compound 56,substituting N-a-Boc-D-cyclohexylalanine.

EXAMPLE 62

A solution of Compound 56 (11 mmol) in 70 mL of dry tetrahydrofuran iscooled to −78° C. and a solution of lithium hexamethyldisilazane intetrahydrofuran (33 mmol) is added via syringe at such a rate that thetemperature did not rise above −60° C. The reaction mixture is warmed to−25° C. over 40 minutes and recooled to −78° C. A solution of3-cyanobenzyl bromide (27 mmol) in 20 mL of tetrahydrofuran is added viasyringe at such a rate that the temperature did not rise above −60° C.The reaction mixture is allowed to come to room temperature and stirredat room temperature for 1 hour. 125 mL of saturated sodium bicarbonateis added and tetrahydrofuran is removed in vacuo. The remaining materialis partitioned between 500 mL of ethyl acetate and 150 mL of saturatedsodium bicarbonate. The organic phase is further washed with saturatedsodium bicarbonate (2×100 mL) and brine. The organic layer is dried overmagnesium sulfate, filtered, concentrated in vacuo. The residue istriturated with 40 mL of 4:1 hexanes:ethyl acetate. The solid materialis filtered off and discarded. The filtrate, containing the desiredproduct, is concentrated in vacuo.

EXAMPLE 63

Compound 63 is prepared following the method described for Compound 62,substituting the product obtained in Example 57.

EXAMPLE 64

Compound 64 is prepared following the method described for Compound 62,substituting the product obtained in Example 58.

EXAMPLE 65

Compound 65 is prepared following the method described for Compound 62,substituting the product obtained in Example 59.

EXAMPLE 66

Compound 66 is prepared following the method described for Compound 62,substituting the product obtained in Example 60.

EXAMPLE 67

Compound 67 is prepared following the method described for Compound 62,substituting the product obtained in Example 61.

EXAMPLE 68

To a solution of Compound 62 (5 mmol) in 60 mL of methylene chloride isadded 20 mL of trifluoroacetic acid, dropwise at 0°C. The resultingsolution is stirred for 2 hours at 0°C. Solvents are removed in vacuoand the residue purified by reverse phase HPLC using a gradient of 30%to 70% acetonitrile in water containing 0.1% trifluoroacetic acid.Acetonitrile is removed in vacuo and the remaining material partitionedbetween saturated sodium bicarbonate and ethyl acetate. The aqueouslayer is extracted twice with ethyl acetate and the combined organiclayers are dried over magnesium sulfate, filtered, and concentrated invacuo.

EXAMPLE 69

Compound 69 is prepared according to the method described in Example 68,substituting the product obtained in Example 63.

EXAMPLE 70

Compound 70 is prepared according to the method described in Example 68,substituting the product 5 obtained in Example 64.

EXAMPLE 71

Compound 71 is prepared according to the method described in Example 68,substituting the product obtained in Example 65.

EXAMPLE 72

Compound 72 is prepared according to the method described in Example 68,substituting the product obtained in Example 66.

EXAMPLE 73

Compound 73 is prepared according to the method described in Example 68,substituting the product obtained in Example 67.

EXAMPLE 74

Solution (A): To a solution of 11.8 mL of n-butyl lithium in hexanes (19mmol) in 13 mL of tetrahydrofuran is added a solution of1-bromo-2-fluorobenzene (19 mmol) in 2 mL of tetrahydrofuran, dropwisevia syringe at −78° C. Stirring at −78° C. is continued for 1 hour. Asolution of zinc chloride (19 mmol) in 38 mL of tetrahydrofuran is addedover 2 minutes at −78° C. The resulting solution is allowed to come toroom temperature over 40 minutes.

Solution (B): To a solution of bis(triphenylphosphine) palladiumdichloride (1mmol) in 11 mL of tetrahydrofuran is added diisobutylaluminum hydride (1mmol) as a solution in hexanes, at room temperature,followed by methyl iodobenzoate(16 mmol) in a single portion at roomtemperature. Solution (A) is added to solution (B) and the reactionmixture allowed to stir at room temperature overnight. The reactionmixture is diluted with 300 mL of diethyl ether and washed with 1Nhydrochloric acid (3×75 mL) and brine. The organic layer is dried overmagnesium sulfate, filtered, and concentrated in vacuo.

EXAMPLE 75

Compound 75 is prepared according to the method described for Compound74, substituting 1-bromo-3-fluorobenzene in the preparation of Solution(A).

EXAMPLE 76

Compound 76 is prepared according to the method described for Compound74, substituting 1-bromo-4-fluorobenzene in the preparation of Solution(A).

EXAMPLE 77

Compound 77 is prepared according to the method described in EXAMPLE 74,substituting 3,4-ethylenedioxy bromobenzene in the preparation ofSolution (A).

EXAMPLE 78

Compound 78 is prepared according to the method described in EXAMPLE 74,substituting 3,4-methylenedioxy bromobenzene in the preparation ofSolution (A).

EXAMPLE 79

Compound 79 is prepared according to the method described in Example 74,substituting 3,4-dimethoxy bromobenzene in the preparation of Solution(A).

EXAMPLE 80

Compound 80 is prepared according to the method described in Example 74,substituting 3-cyano bromobenzene in the preparation of Solution (A).

EXAMPLE 81

Ammonia gas is bubbled into a suspension of Compound 80 (24 mmol) in 200mL of methanol for five minutes. To the resulting solution is addedrhodium on alumina (5 g) and the suspension is shaken under a positivepressure of hydrogen for 36 hours. Catalyst is filtered off and methanolis removed in vacuo to give an oil which is triturated with ether andfiltered.

EXAMPLE 82

A solution of Compound 81(15.4 mmol), triethylamine (17 mmol),di-tert-butyl dicarbonate (15.4 mmol), and 4-dimethylaminopyridine (1.5mmol) in 60 mL of dimethylformamide is stirred at room temperatureovernight. The solution is diluted with 800 mL of ethyl acetate andwashed with 1N hydrochloric acid (3×150 mL) and brine. The organic layeris dried over magnesium sulfate, filtered, concentrated in vacuo, andpurified by flash chromatography (3:2 hexanes:ethyl acetate).

EXAMPLE 83

A solution of Compound 81 (2 mmol), acetic anhydride (8 mmol), anddimethylamino pyridine (0.2 mmol) in 20 mL of pyridine is stirred atroom temperature overnight. The reaction mixture is poured into 200 mLof 5% hydrochloric acid and extracted with ethyl acetate (3×200 mL). Thecombined organic extracts are dried over magnesium sulfate, filtered,concentrated in vacuo, and purified by flash chromatography (3:1hexanes:ethyl acetate).

EXAMPLE 84

Compound 84 is prepared according to the method described for Compound74, substituting 4-cyano bromobenzene in the preparation of Solution(A).

EXAMPLE 85

Compound 85 is prepared according to the method described for Compound81, substituting the product obtained in Example 84.

EXAMPLE 86

Compound 86 is prepared according to the method described for Compound82, substituting the product obtained in Example 85.

EXAMPLE 87

Compound 87 is prepared according to the method described for Compound83, substituting the product obtained in Example 85.

EXAMPLE 88

To a solution of methyl coumalate (6.5 mmol) and 3-nitrostyrene (32.5mmol) in 30 mL of m-xylene is added 10% palladium on carbon (2.5 g) in asingle portion. The reaction mixture is heated at 140° C. overnight.After cooling, the reaction mixture is filtered through celite and thefiltrate concentrated in vacuo. The resulting slurry is triturated with3:1 hexanes:ethyl acetate. The solid, which is the desired product, isremoved by filtration.

EXAMPLE 89

Compound 89 is prepared using a method identical to the one used forCompound 88, substituting 4-nitrostyrene.

EXAMPLE 90

To a flask containing 100 mL of fuming nitric acid is added 4-biphenylcarboxylic acid (20 mmol), portionwise at 0° C. Stirring is continued 15minutes at 0° C. Water (100 mL) is slowly added and the filtratecollected and recrystallized from ethanol.

EXAMPLE 91

Compound 91 is prepared according to the method described for Compound74, substituting 3-benzyloxy bromobenzene in the preparation of Solution(A).

EXAMPLE 92

Compound 92 is prepared according to the method described for Compound74, substituting 4-benzyloxy bromobenzene in the preparation of Solution(A).

EXAMPLE 93

To a suspension of Compound 74 (1.6 mmol) in 10 mL of methanol and 20 mLof tetrahydrofuran is added 10 mL of 2N sodium hydroxide, dropwise atroom temperature. The resulting solution is allowed to stir at roomtemperature for 2 hours. Organic solvents are removed in vacuo and theresidue diluted with 20 mL of water and brought to pH 2 with 1Nhydrochloric acid. Solid material is filtered off and dried undervacuum.

EXAMPLE 94

Compound 94 is prepared according to the method described for 93,substituting the product obtained in Example 75.

EXAMPLE 95

Compound 95 is prepared according to the method described for Compound93, substituting the product obtained in Example 76.

EXAMPLE 96

Compound 96 is prepared according to the method described for Compound93, substituting the product 5 obtained in Example 77.

EXAMPLE 97

Compound 97 is prepared according to the method described for Compound93, substituting the product obtained in Example 78.

EXAMPLE 98

Compound 98 is prepared according to the method described for Compound93, substituting the product obtained in Example 79.

EXAMPLE 99

Compound 99 is prepared according to the method described for Compound93, substituting the product obtained in Example 82.

EXAMPLE 100

Compound 100 is prepared according to the method described for Compound93, substituting the product obtained in Example 83.

EXAMPLE 101

Compound 101 is prepared according to the method described for Compound93, substituting the product obtained in Example 86.

EXAMPLE 102

Compound 102 is prepared according to the method described for Compound93, substituting the product obtained in Example 87.

EXAMPLE 103

Compound 103 is prepared according to the method described for Compound93, substituting the product obtained in Example 88.

EXAMPLE 104

Compound 104 is prepared according to the method described for Compound93, substituting the product obtained in Example 89.

EXAMPLE 105

Compound 105 is prepared according to the method described for Compound93, substituting the product obtained in Example 91.

EXAMPLE 106

Compound 106 is prepared according to the method described for Compound93, substituting the product obtained in Example 90.

EXAMPLE 107

To a solution of Compound 96 (2 mmol) in 10 mL of DMF is addeddiisopropyl ethylamine (2 mmol) in a single portion at room temperature,followed by 2-(1H-benzotriazol-1-yl) 1,1,3,3-tetramethyluroniumtetrafluoroborate (2 mmol) in a similar fashion. The reaction mixture isstirred for 2 minutes at room temperature and a solution of Compound 70(2 mmol) in 15 mL of dimethylformamide is added in a single portion.Stirring is continued overnight at room temperature. The reactionmixture is diluted with 300 mL of ethyl acetate and washed sequentiallywith 1N hydrochloric acid (3×75 mL), water, saturated sodium bicarbonate(3×75 mL) and brine. The organic phase is dried over magnesium sulfate,filtered and concentrated in vacuo.

EXAMPLE 108

Compound 108 is prepared using the same procedure described for Compound107, substituting Compound 93 for Compound 96.

EXAMPLE 109

Compound 109 is prepared using the same procedure described for Compound107, substituting Compound 94 for Compound 96.

EXAMPLE 110

Compound 110 is prepared using the same procedure described for Compound107, substituting Compound 95 for Compound 96.

EXAMPLE 111

Compound 111 is prepared using the same procedure described for Compound107, substituting 4-biphenyl carboxylic acid for Compound 96 andsubstituting Compound 68 for Compound 70.

EXAMPLE 112

Compound 112 is prepared using the same procedure described for Compound107, substituting Compound 97 for Compound 96.

EXAMPLE 113

Compound 113 is prepared using the same procedure described for Compound107, substituting Compound 98 for Compound 96.

EXAMPLE 114

Compound 114 is prepared using the same procedure described for Compound107, substituting Compound 99 for Compound 96 and substituting Compound68 for Compound 70.

EXAMPLE 115

Compound 115 is prepared using the same procedure described for Compound107, substituting Compound 100 for Compound 96 and substituting Compound68 for Compound 70.

EXAMPLE 116

Compound 116 is prepared using the same procedure described for Compound107, substituting Compound 101 for Compound 96 and substituting Compound68 for Compound 70.

EXAMPLE 117

Compound 117 is prepared using the same procedure described for Compound107, substituting Compound 102 for Compound 96 and substituting Compound68 for Compound 70.

EXAMPLE 118

Compound 118 is prepared using the same procedure described for Compound107, substituting Compound 103 for Compound 96 and substituting Compound68 for Compound 70.

EXAMPLE 119

Compound 119 is prepared using the same procedure described for Compound107, substituting Compound 104 for Compound 96 and substituting Compound68 for Compound 70.

EXAMPLE 120

Compound 120 is prepared using the same procedure described for Compound107, substituting Compound 90 for Compound 96 and substituting Compound68 for Compound 70.

EXAMPLE 121

Compound 121 is prepared using the same procedure described for Compound107, substituting Compound 105 for Compound 96 and substituting Compound68 for Compound 70.

EXAMPLE 122

Compound 122 is prepared using the same procedure described for Compound107, substituting Compound 106 for Compound 96 and substituting Compound68 for Compound 70.

EXAMPLE 123

Compound 123 is prepared using the same procedure described for Compound107, substituting Compound 99 for 96 and substituting Compound 69 forCompound 70.

EXAMPLE 124

Compound 124 is prepared using the same procedure described for Compound107, substituting Compound 99 for Compound 96 and substituting Compound73 for Compound 70.

EXAMPLE 125

Compound 125 is prepared using the same procedure described for Compound107, substituting Compound 99 for Compound 96 and substituting Compound71 for Compound 70.

EXAMPLE 126

Compound 126 is prepared using the same procedure described for Compound107, substituting Compound 99 for Compound 96 and substituting Compound72 for Compound 70.

EXAMPLE 127

Compound 127 is prepared using the same procedure described for Compound107, substituting indole-6-- carboxylic acid for Compound 96 andsubstituting Compound 69 for Compound 70.

EXAMPLE 128

Compound 128 is prepared using the same procedure described for Compound107, substituting indole-5-carboxylic acid for Compound 96 andsubstituting Compound 69 for Compound 70.

EXAMPLE 129

To a solution of Compound 107 (1.2 mmol) in 10 mL of methanol and 10 mLof tetrahydrofuran is added 10 mL of 2N sodium hydroxide, dropwise at 0°C. The solution is allowed to come to room temperature and stirred atroom temperature for 2.5 hours. The solution is cooled to 0C and 1Nhydrochloric acid is added until the pH is 7. Organic solvents areremoved in vacuo and the residue diluted with 25 mL of water. 1Nhydrochloric acid is added to bring the pH down to 2 and the mixture isextracted with ethyl acetate (3×75 mL). The combined organic extractsare dried over magnesium sulfate, filtered, concentrated, and driedunder vacuum. The acid (1.1 mmol) is dissolved in 15 mL oftetrahydrofuran and cooled to −20° C. N-methyl morpholine (1.45 mmol) isadded in a single portion, followed by isobutyl chloroformate (1.45mmol) dropwise via syringe. The reaction mixture is allowed to stir at−20° C. for 20 minutes. The reaction mixture is filtered into a solutionof sodium borohydride (11 mmol) in 20 mL of water at 0° C. Stirring iscontinued 1.5 hours at 0° C. The reaction mixture is diluted with 300 mLof ethyl acetate and washed with water (3×100 mL) and brine. The organicphase is dried over magnesium sulfate, filtered, and concentrated. Theresulting alcohol is purified by flash chromatography (2:3 ethylacetate:hexanes).

EXAMPLE 130

Compound 130 is prepared following the procedure described for Compound129, substituting Compound 108 for Compound 107.

EXAMPLE 131

Compound 131 is prepared following the procedure described for Compound129, substituting Compound 109 for Compound 107.

EXAMPLE 132

Compound 132 is prepared following the procedure described for Compound129, substituting Compound 110 for Compound 107.

EXAMPLE 133

Compound 133 is prepared following the procedure described for Compound129, substituting Compound 112 for Compound 107.

EXAMPLE 134

Compound 134 is prepared following the procedure described for Compound129, substituting Compound 113 for Compound 107.

EXAMPLE 135

Compound 135 is prepared following the procedure described for Compound129, substituting Compound 114 for Compound 107.

EXAMPLE 136

Compound 136 is prepared following the procedure described for Compound129, substituting Compound 115 for Compound 107.

EXAMPLE 137

Compound 137 is prepared following the procedure described for Compound129, substituting Compound 116 for Compound 107.

EXAMPLE 138

Compound 138 is prepared following the procedure described for Compound129, substituting Compound 117 for Compound 107.

EXAMPLE 139

Compound 139 is prepared following the procedure described for Compound129, substituting Compound 118 for Compound 107.

EXAMPLE 140

Compound 140 is prepared following the procedure described for Compound129, substituting Compound 119 for Compound 107.

EXAMPLE 141

Compound 141 is prepared following the procedure described for Compound129, substituting Compound 120 for Compound 107.

EXAMPLE 142

Compound 142 is prepared following the procedure described for Compound129, substituting Compound 121 for Compound 107.

EXAMPLE 143

Compound 143 is prepared following the procedure described for Compound129, substituting Compound 122 for Compound 107.

EXAMPLE 144

Compound 144 is prepared following the procedure described for Compound129, substituting Compound 123 for Compound 107.

EXAMPLE 145

Compound 145 is prepared following the procedure described for Compound129, substituting Compound 124 for Compound 107.

EXAMPLE 146

Compound 146 is prepared following the procedure described for Compound129, substituting Compound 125 for Compound 107.

EXAMPLE 147

Compound 147 is prepared following the procedure described for Compound129, substituting Compound 126 for Compound 107.

EXAMPLE 148

To a solution of Compound 129 (0.5 mmol) in 8 mL of methylene chlorideis added pyridine (0.6 mmol) in a single portion at 0° C. Aceticanhydride (0.6 mmol) is added in a single portion, followed bydimethylaminopyridine in a similar fashion. The reaction mixture isallowed to come to room temperature and stirring is continued overnight.The reaction mixture is partitioned between 10 mL of 0.1N hydrochloricacid and 30 mL of methylene chloride. The organic layer is dried oversodium sulfate, filtered and concentrated in vacuo.

EXAMPLE 149

Compound 149 is prepared following the method described for Compound148, substituting Compound 130 for Compound 129.

EXAMPLE 150

Compound 150 is prepared following the method described for Compound148, substituting Compound 131 for Compound 129.

EXAMPLE 151

Compound 151 is prepared following the method described for Compound148, substituting Compound 132 for Compound 129.

EXAMPLE 152

Compound 152 is prepared following the method described for Compound148, substituting Compound 133 for Compound 129.

EXAMPLE 153

Compound 153 is prepared following the method described for Compound148, substituting Compound 134 for Compound 129.

EXAMPLE 154

To a solution of Compound 135 (1.1 mmol) in 30 mL of methylene chlorideis added 10 mL of trifluoroacetic acid in a single portion at 0° C. Theresulting solution is stirred for 3 hours at 0° C. Solvents are removedin vacuo and the residue partitioned between 10% aqueous sodiumbicarbonate and ethyl acetate. The organic phase is dried over magnesiumsulfate, filtered, and concentrated in vacuo. The free amine (1.1 mmol)is dissolved in 10 mL of glacial acetic acid and paraformaldehyde (11mmol) is added in a single portion at room temperature. Stirring iscontinued overnight at room temperature. The reaction mixture is pouredinto 50 mL of ice cold 2N sodium hydroxide and extracted with ethylacetate (3×100 mL). The combined organic extracts are backwashed withwater, dried over magnesium sulfate, filtered, and concentrated invacuo. The desired product is purified by reverse phase HPLC using agradient of 20% to 100% acetonitrile in water, buffered with 0.1%trifluoroacetic acid.

EXAMPLE 155

To a solution of Compound 154 (0.5 mmol) in 10 mL of dry acetone isadded methyl iodide (large excess, 2 mL) in a single portion at roomtemperature. The resulting solution is allowed to stir at roomtemperature overnight. Solvents are removed in vacuo to provide thedesired tetramethylammonium salt.

EXAMPLE 156

To a solution of Compound 111 (0.8 mmol) in 2 mL of dimethylformamideand 8 mL of tetrahydrofuran is added sodium hydride (1 mmol) in a singleportion at 0° C. The solution is stirred for 1 hour at 0° C. and methyliodide (large excess) is added in a single portion. The solution isallowed to come to room temperature and stirred overnight. The reactionmixture is poured into 100 mL of ice water and extracted with ethylacetate (3×75 mL). The combined organic extracts are backwashed withwater, dried over magnesium sulfate, filtered, concentrated in vacuo,and purified by flash chromatography (1:2 ethyl acetate:hexanes).

EXAMPLE 157

Compound 157 is prepared following the procedure described for Compound154, substituting Compound 123 for 135.

EXAMPLE 158

Compound 158 is prepared according to the method described for Compound155, starting from Compound 157.

EXAMPLE 159a

To a solution of Compound 129 (1 mmol) in 50 mL of dry methanol is addedcrushed 3 Å molecular sieves (approximately 1 g). The mixture is stirredfor 10 minutes at 0° C. and hydrogen chloride gas is bubbled through thereaction mixture for 10 minutes at 0° C. The reaction mixture is allowedto come to room temperature and stirred overnight. Nitrogen gas isbubbled through the reaction mixture for 5 minutes and methanol isremoved in vacuo. The residue is dried under vacuum to remove all tracesof hydrogen chloride, then remixed with 75 mL of dry methanol. Themixture is then cooled to 0° C. and ammonia gas is bubbled through thereaction mixture for 10 minutes. The reaction mixture is allowed to cometo room temperature, then heated at 60° C. for 3 hours. After cooling toroom temperature, nitrogen gas is bubbled through the reaction for 5minutes and the mixture is filtered through celite, concentrated invacuo, and purified by reverse phase HPLC using a gradient of 20% to 80%acetonitrile in water buffered with 0.1% trifluoroacetic acid.Acetonitrile is removed in vacuo and the aqueous phase lyophilized toprovide the desired product as its trifluoroacetate salt.

EXAMPLE 159b

¹H NMR (300 MHz, d6 DMSO) δ9.21 (s, 2H), 9.01 (s, 2H), 8.22 (d, 1H,J=9.6 Hz), 7.85 (d, 2H,J=7.2 Hz), 7.70 (d, 2H, J=7.2 Hz), 7.62-7.38 (m,4H), 7.25-7.05 (m, 7H), 6.93 (d, 1H, J=8.4 Hz), 4.90-4.65 (m, 1H), 4.24(s, 4H), 4.18-4.05 (m, 2H), 2.78-2.63 (m, 2H), 2.65-2.45 (m, 2H),2.08-1.75 (m, 3H). MS, LRFAB, calc.591, found 592 (M+H)+.

Into a solution of Compound 129 (1 mmol) in 20 mL of pyridine and 4 mLof triethylamine is bubbled hydrogen sulfide for 10 minutes at roomtemperature. The solution is allowed to stir at room temperatureovernight. Nitrogen gas is bubbled through the reaction for 5 minutesand solvents are removed in vacuo. The residue is dried under vacuum,then dissolved in 15 mL of dry acetone. To this solution is added 5 mLof methyl iodide and this solution is heated at 50° C. for 1 hour, thenconcentrated in vacuo. The residue is dissolved in 20 mL of methanol andammonium acetate (2 mmol) is added in a single portion at roomtemperature. The reaction mixture is heated at 65° C. for 2 hours. Aftercooling, methanol is removed in vacuo and the residue purified byreverse phase HPLC using a gradient of 20% to 80% acetonitrile in waterbuffered with 0.1% trifluoroacetic acid. Acetonitrile is removed invacuo and the aqueous phase lyophilized to provide the desired productas its trifluoroacetate salt.

The following compounds are prepared from the appropriate startingmaterials by procedures substantially similar to the proceduresdescribed above.

EXAMPLE 161

¹H NMR (300 MHz, d6 DMSO) δ9.23 (s, 2H), 9.01 (s 2H), 8.27 (d, 1H, J=9.6Hz), 7.93 (d, 2H, J=7.2 Hz), 7.72 (d, 2H, J=7.2 Hz), 7.65-7.55 (m, 2H),7.54-7.42 (m, 2H), 7.28-7.08 (m, 7H), 6.94 (d, 1H, J=8.4 Hz), 4.25 (s,4H), 4.24-4.11 (m, 1H), 4.05-3.83 (m,2H), 2.86 (dd, 1H, J=6.0, 15.6 Hz),2.07-2.55 (m, 2H), 2.53-2.43 (m, 1H), 2.35-2.20 (m,1H), 1.98-1.90 (m,2H), 1.87 (s, 3H). MS, LRFAB, calc. 591, found 592 (M+H)+.

EXAMPLE 162

¹H NMR (300 MHz, d6 DMOS) δ9.21 (s, 2H), 9.01 (s, 2H), 8.22 (d, 1H,J=9.6 Hz), 7.85 (d, 2H,J=7.2 Hz), 7.70 (d, 2H, J=7.2 Hz), 7.62-7.38 (m,4H), 7.25-7.05 (m, 7H), 6.93 (d, 1H, J=8.4 Hz), 4.90-4.65 (m, 1H), 4.24(s, 4H), 4.18-4.05 (m, 2H), 2.78-2.63 (m, 2H), 2.65-2.45 (m, 2H),2.08-1.75 (m, 3H). MS, LRFAB, calc.591, found 592 (M+H)⁺.

EXAMPLE 163

¹H NMR 300 MHz, d6 DMSO, δ9.23 (s, 2H), 9.09 (s, 2H), 8.83 (d, 1H,J=9.96 Hz), 7.97 (d, 2H, J=7.2 Hz), 7.83 (d, 1H, J=7.2 Hz), 7.65-7.35(m, 7H), 7.28-7.05 (m, 6H), 4.26-4.10 (m, 1H), 4.05-3.83 (m, 2H), 2.87(dd, 1H, J=6.0 Hz,15.6 Hz), 2.70-2.55 (m, 2H), 2.32-2.18 (m, 1H),2.03-1.90 (m, 2H), 1.87(s, 3H). MS ion spray: calc. 551, found 552(M+H)+.

EXAMPLE 164

¹H NMR 300 MHz, d6 DMSO, δ9.22 (s, 2H), 9.02 (s, 2H), 8.32 (d, 1H, J=9.6Hz), 7.96 (d, 2H, J=7.2 Hz), 7.81-7.65 (m, 4H), 7.65-7.40 (m, 4H),7.38-7.05 (m, 7H), 4.2-4.10 (m, 1H), 4.05-3.85 (m, 2H), 2.87 (dd, 1H,J=6.0,15.6 Hz), 2.70-2.55 (m, 2H), 2.54-2.43 (m, 1H), 2.35-2.20 (m, 1H),1.98-1.90 (m, 2H), 1.89 (s, 3H). MS ion spray: calc. 551, found 552(M+H)+.

EXAMPLE 165

¹H NMR, 300 MHz, d6 DMSO, δ9.25 (s, 2H), 9.18 (s, 2H), 8.35 (d, 1H,J=9.6 Hz), 7.80 (d, 2H, 7.2 Hz), 7.73 (d, 2H, J=7.2 Hz), 7.68 (d, 2H,J=6.0 Hz), 7.62 (br.s, 2H), 7.55-7.03 (m, 5H), 4.65-4.45 (m, 1H),3.53(s, 3H), 3.20-2.82 (m, 5H). MS LRFAB: cal'd505 (M+H)+.

EXAMPLE 166

¹H NMR (300 MHz, d6 DMSO) δ9.23 (s, 2H), 8.99 (s, 2H), 8.26 (d, 1H,J=9.6 Hz), 7.93 (d, 2H, J=7.2 Hz), 7.72 (d, 2H, J=7.2 Hz), 7.65-7.56 (m,2H), 7.54-7.42 (m, 2H), 7.32 (d, 1H, J=2.4 Hz), 7.28-7.08 (m, 6H), 7.02(d, 1H, J=8.4 Hz), 6.07 (s, 2H), 4.25-4.12 (m, 1H), 4.06-3.85 (m, 2H),2.85 (dd, 1H, J=6.0, 15.6 Hz), 2.68-2.55 (m, 2H), 2.53-2.43 (m, 1H),2.32-2.20 (m, 1H), 2.01-1.90 (m, 2H), 1.87 (s, 3H). MS, LRFAB, calc.557,found 558 (M+H)+.

EXAMPLE 167

¹H NMR: 9.5 (s, 1H), 9.4 (s, 1H), 8.4 (d, ¹H J=9.0 Hz), 8.1 (d, 2H,J=8.0 Hz), 7.9 (d, 2H, J=8.0 Hz), 7.5-7.8 (m, 5H), 7.1-7.4 (m, 7H), 5.0(m, 1H), 4.0-4.1 (m, 1H), 4.0 (s, 3H), 3.9 (s, 3H), 3.6 (m, 1H), 2.9-3.1(m, 4H), 2.1-2.3 (m, 2H), 2.0 (s, 3H). M.S. Cal'd 594.3, Found 594.

EXAMPLE 168

¹H NMR: 9.4 (s, 1H), 9.0 (s, 1H), 8.4 (d, 1H, J=9.0 Hz), 8.1 (d, 2H,J=7.0 Hz), 7.9 (d, 2H, J=7.0 Hz), 7.5-7.8 (m, 5H), 7.1-7.4 (m, 7H), 5.0(m, 1H), 4.0-4.1 (m, 1H), 4.0 (s, 3H), 3.9 (s, 3H), 3.6 (m, H), 2.9-3.1(m, 4H), 2.1-2.3 (m, 2H). M.S. Cal'd 552.1, Found 552

EXAMPLE 169

¹H NMR, 300 MHz, d6 DMSO, δ9.22 (s, 2H), 9.11 (s, 2H), 7.92 (d, 2H,J=7.2 Hz), 7.80-7.65 (m, 4H), 7.62-7.40 (m, 4H), 7.37-7.01 (m, 7H),4.85-4.65 (m, 1H), 4.22-4.0 (m, 1H), 3.55-3.36 (m, 2H), 2.82-2.62 (m,2H), 2.60-2.45 (m, 1H), 2.05-1.73 (m, 3H). MS LRFAB: calc. 509, found510 (M+H).

EXAMPLE 170

¹H NMR: 8.5 (d, 1H, J=9.0 Hz), 7.8 (d, 2H, J=9.0 Hz), 7.7 (d, 2H, J=9.0Hz), 7.1-7.6 (m, 11H), 4.5 (m, 1H), 4.4 (s, 2H), 4.0 (dd, 1H, J=6.0Hz,10.0 Hz), 3.7 (dd, 1H,(J=6.0 Hz, 10.0 Hz), 3.0 (d, 2H, J=9.0 Hz), 2.9(d, 2H, J=9.0 Hz), 2.0 (d, 1H, J=7.0 Hz). Mass spec M+H calc 549.2,found 549.

EXAMPLE 171

¹H NMR: 8.5 (d, 1H, J=9.0 Hz), 7.75-7.9 (m, 6H), 7.4-7.7 (m, 6H),7.0-7.2 (m, 5H), 4.4(m, 1H), 4.2 (s, 2H), 4.0 (dd, 1H, (J=6.0 Hz,10.0Hz), 3.7 (dd, 1H, J=6.0 Hz,10.0 Hz), 3.0 (d, 2H, (J=9.0 Hz), 2.9 (d, 1H,(J=9.0 Hz), 2.0 (m, 1H). Mass spec M+H calc 507.3, found 507.

EXAMPLE 172

¹H NMR: 8.5 (d, 1H, J=9.0 Hz), 7.8 (d, 2H, J=10.0 Hz), 7.7 (d, 2H,J=10.0 Hz), 7.6 (d, 1H, J=10.0 Hz), 7.5 (m, 3H), 7.0-7.3 (m, 8H), 6.8(d, 1H, J=9.0 Hz), 4.5 (m, 3H), 4.1 (dd, 1H, J=6.0 Hz, 10.0 Hz), 3.9(dd, H J=6.0 Hz, 10.0 Hz), 3.1 (d, 2H,J=9.0 Hz) 2.9 (d, 2H,J9.0 Hz), 2.0(m, 1H). Mass. Spec M+H calc 492.2, found 494.

EXAMPLE 173

¹H NMR: 8.5 (d, 1H, J=9.0 Hz), 7.9 (d, 2H, J=10.0 Hz), 7.8 (d, 2H,J=10.0 Hz), 7.7 (d, 2H, J=10.0 Hz), 7.6 (d, 2H, J=10.0 Hz), 7.4 (s, 1H),7.0-7.2 (m, 3H), 4.5 (m, 3H), 4.1 (dd, H, J=6.0 Hz, 10.0 Hz), 3.9 (dd,¹H J=6.0 Hz,10.0 Hz), 3.1 (d, 2H, J=9.0 Hz) 2.9 (d, 2H,J=9.0 Hz), 2.1(d, 3H, J=10.0 Hz). Mass Spec M+H calc 549.3, found 549.

EXAMPLE 174

¹H NMR: 8.5 (d, 1H, J=9.0 Hz), 7.8 (d, 2H, J=8.0 Hz), 7.6-7.8 (m, 4H),7.4-7.6 (m, 4H), 7.1-7.3 (m, 4H), 6.8 (d, 2H, J=9.0 Hz), 4.3 (m, 1H),4.0 (dd, 1H, J=6.0 Hz,10.0 Hz), 3.7 (dd, 1H, J=6.0 Hz, 10.0 Hz), 3.0 (d,2H, J=4.0 Hz), 2.9 (d, 1H, J=9.0 Hz), 2.0 (m, 1H). Mass spec. M+H calc507.3, found 507

EXAMPLE 175

M.S. Cal'd 494.2, Found 494

EXAMPLE 176

¹H NMR 300 MHz, d6 DMSO δ9.23 (s, 2H), 9.04 (s, 2H), 8.57 (d, 1H, 9.6Hz), 8.42 (s, 1H), 8.32 (d, 2H, 7.2 Hz), 8.13 (dd, 1H, J=1.2, 7.2 Hz),7.75-7.40 (m, 7H), 7.25-7.13 (m, 4H), 7.12-7.05 (m, 2H), 4.48-4.35 (m,1H), 3.58-3.42 (m, 2H), 3.10-2.62 (m, 4H), 2.15-1.95 (m, 1H). MS(LRFAB): calc. 567, found 568 (M+H)+.

EXAMPLE 177

¹H NMR 300 MHz, d6 DMSO δ9.23 (s, 2H), 8.98 (s, 2H), 8.37-8.22 (m,3H),7.97 (d, 2H, J=7.2 Hz), 7.86 (s, 4H),7.65-7.40 (m, 4H), 7.25-7.15 (m,3H), 7.13-7.05 (m, 2H), 4.45-4.25 (m, 1H), 3.62-3.48 (m, 2H), 3.00-2.86(m, 2H), 2.85-2.65 (m, 2H), 2.06-1.92 (m, 1H). MS (LRFAB): calc. 522,found 523 (M+H)+.

EXAMPLE 178

¹H NMR 300 MHz, d6 DMSO,9.23(d,4H,J=6 Hz), 8.28(d,1H,J=10 Hz),7.77(d,2H,J=10 Hz), 7.71-7.42(m,8H),7.22-7.12(m,4H), 7.10-7.01(m,3H),4.45-4.25(m, 1H), 3.65-3.45 (m,2H), 3.05-2.87(m,2H),2.85-2.65(m,2H),2.05-1.95(m,1H). MS (LRFAB): calc'd 492, found 493 (M+H)+.

EXAMPLE 179

¹H NMR 300 MHz, d6 DMSO, 9.38-9.21(m,4H), 8.28(d,1H,J=10 Hz), 8.16(d,1H,J=10 Hz), 7.70-7.45 (m,5H), 7.42(d,2H,J=7 Hz), 7.23(s,1H),7.21-7.03(m,8H), 4.48-4.23(m, 1H), 3.64-3.40(m,2H), 3.10-2.85(m,2H),2.84-2.62(m,2H), 2.03-1.87(m,1H). MS (LRFAB): calc'd 507, found 508(M+H)+.

EXAMPLE 180

¹H NMR 300 MHz, d6 DMSO, 9.23 (s, 2H), 8.95 (s, 2H), 8.45 (s, 1H), 8.32(d, 1H, J=8.4 Hz), 8.24 (d, 1H, J=8.4 Hz), 8.18 (d, 1H, J=7.2 Hz), 7.86(br.s, 4H), 7.83-7.73 (m, 1H), 7.63-7.43 (m, 4H), 7.25-7.16 (m , 4H),7.14-7.05 (m, 1H), 4.45-4.30 (m, 1H), 3.63-3.48 (m, 2H), 3.63-3.48 (m,2H), 3.02-2.88 (m, 2H), 2.87-2.65 (m, 2H), 2.08-1.93 (m, 1H). MS(LRFAB):calc'd 522, found 523 (M+H)+.

EXAMPLE 181

¹H NMR 300 MHz, d6 DMSO, 9.25 (s, 2H), 9.19 (s, 2H), 8.30 (d, 1H, J=9.6Hz), 7.82 (s, 1H), 7.82 (d, 2H ,J=7.2 Hz), 7.66 (d, 2H, J=7.2 Hz),7.63-7.45 (m, 4H), 7.38-7.27 (m, 1H), 7.25-7.13 (m, 6H), 7.13-7.05 (m,1H), 6.93 (d, 1H, J=8.4 Hz), 4.43-4.28 (m, 1H), 3.65-3.45 (m, 2H),3.05-2.86 (m, 2H), 2.83-2.68 (m, 2H), 2.08-1.92 (m, 1H). MS(LRFAB):calc'd 492, found 493 (M+H)+.

EXAMPLE 182

¹H NMR 300 MHz, d6 DMSO, 9.22(s,2H), 9.07(s,2H), 8.38(d,1H,J=10 Hz),7.93 (s,1H), 7.93(s,1H), 7.83(d,2H,J=7 Hz), 7.65(d,2H,J=7 Hz),7.62-7.45(m,5H), 7.42-7.28(m,2H), 7.25-7.16(m, 4), 7.13-7.07 (m,1H),4.45-4.28(m,1H), 3.63-3.53(m,2H), 3.05-2.87(m,2H), 2.85-2.68(m, 2H),2.03(s, 3H), 2.02-1.93 (m,1H). MS(LRFAB): calc'd 534, found 535 (M+H)+.

EXAMPLE 183

¹H NMR 300 MHz, d6 DMSO, 10.5(s,1H),9.23(s,2H), 9.10(s,2H),8.25(d,1H,J=10 Hz), 7.78(d,2H,J=7 Hz),7.73-7.40(m,10H), 7.21-7.13(m,4H),7.13-7.05(m, 1H), 4.43-4.25(m, 1H), 3.63-3.45(m,2H), 3.03-2.85(m,2H),2.83-2.68(m,2H), 2.04(s,3H), 2.01-1.93(m,1H). MS(LRFAB): calc'd 534,found 535 (M+H)+.

EXAMPLE 184

¹H NMR: 8.5 (d, 1H, J=7.0 Hz), 7.8-8.0 (m, 6H), 7.4-7.7 (M, 6H), 7.1-7.3(m, 5H) 4.6 (m, 3H),4.1 (dd, 1H, J=6.0 Hz,10.0 Hz), 3.7 (dd, 1H, J=6.0Hz,10.0 Hz), 3.0 (d, 2H, J=9.0 Hz), 2.9 (d, 2H, J=9.0 Hz), 2.9 (s, 6H),2.0 (m, 1H). Mass Spec M+H calc 535.3, found 535.

EXAMPLE 185

¹H NMR: 8.5 (d, 1H, J=7.0 Hz), 7.8-8.0 (m, 6H), 7.4-7.7 (M, 6H), 7.1-7.3(m, 5H), 4.6 (m, 3H), 4.0 (dd, 1H, J=6.0 Hz, 10.0 Hz), 3.6 (dd, 1H,J=6.0 Hz), 10.0 Hz), 3.2 (s, 9H), 3.0 (d, 2H, J=9.0 Hz), 2.9 (d, 2H,J=9.0 Hz), 2.0 (m, 1H). Mass Spec M+H calc 549.3, found 549.

EXAMPLE 186

¹H NMR (300 MHz, d6 DMSO), δ9.30-9.11 (m, 3H), 8.31 (br.s, 2H), 8.15 (d,1H, J=8.4 Hz), 7.93 (d, 2H, J=7.2 Hz), 7.86-7.68 (m, 2H), 7.64-7.48 (m,6H), 4.30-4.15 (m, 1H), 4.14-4.04 (m, 2H), 2.75 (d, 2H, J=6.0 Hz),1.95-1.82 (m, 1H), 1.80-1.68 (m, 2H), 1.65-1.46 (m, 5H), 1.42-1.32 (m,1H), 1.31-1.15(m, 1H), 1.13-0.93 (m, 2H), 0.92-0.65 (m, 4H). MS, LRFAB,calc'd. 512, found 513 (M+H)+.

EXAMPLE 187

¹H NMR: 9.0 (s, 1H), 8.5 (d, 1H, J=9.0 Hz), 7.9 (d, 2H, J=9.0 Hz),7.6-7.8 (m, 4H), 7.3-7.5(m, 6H), 7.2-7.1 (m, 6H), 3.5 (s, 3H), 3.1 (s,3H), 3.0 (d, 2H, J=8.0 Hz), 2.9 (d, 2H, J=8.0 Hz). M.S. Cal'd 520.1,Found 520.

EXAMPLE 188

¹H NMR: 9.4 (d, 1H, J=12.0 Hz), 8.6 (d, 1H, J=10.0 Hz), 8.1 (d, 2H,J=10.0 Hz), 7.9-8.1 (m, 4), 7.6-7.8 (m, 6H), 4.7 (m, 1H) 4,4 (d, 2H,J=9.0 Hz), 3.7 (s, 3H), 3.1-3.4 (m, 4H), 1.6 (d, 3H,J=9.0 Hz). Mass SpecM+H calc 459.2 found 459.

EXAMPLE 189

¹H NMR: 9.4 (d, 1H, J=12.0 Hz), 8.0 (d, 1H, J=10.0 Hz), 8.1 (d, 2H,J=10.0 Hz), 7.7-7.9 (m,4H), 7.47-7.6 (m, 6H), 4.5(m, 1H), 4.2 (d,2H,J=9.0 Hz), 3.6 (s, 3H), 3.0-3.2 (m, 3H), 1.6 (d, 3H,J=9.0 Hz). Mass SpecM+H calc 475.1, found 475.

EXAMPLE 190

¹H NMR: 8.4 (d, 1H, J=9.0 Hz), 7.9 (d, 2H, J=10.0 Hz), 7.7-7.9 (m,4H),7.4-7.6 (m, 6H), 4.6 (m,H), 4.5 (s,2H), 3.6 (s, 3H), 3.1-3.2 (m, 3H),2.9 (s,6H), 1.3 (d, 3H,J=9.0 Hz). Mass Spec M+H calc 459.2 found 459.

EXAMPLE 191

¹H NMR: 9.3 (d, 1H, J=9.0 Hz), 9.1 (d, 1H, J=9.0 Hz), 8.4 (d, 1H, J=10.0Hz), 7.7-8.0 (m,4H), 7.3-7.6 (m, 5H), 4.6 (s, 2H), 4,4 (m, 1H), 3.5 (s,3H), 3.1 (s,9H), 2.9-3.1 (m, 3H), 1.6 (d, 3H, J=9.0 Hz). Mass Spec M+Hcalc 501.1 found 501.

EXAMPLE 192

M.S., APCI Cal'd 392, Found 393 (M+H)⁺.

EXAMPLE 193

M.S., APCI Cal'd 392, Found 393 (M+H)⁺.

EXAMPLE 194

¹H NMR: 9.4 (d, 1H, J=12.0 Hz), 8.6 (d, 1H, J=10.0 Hz), 8.0 (d, 2H,J=9.0 Hz), 7.7 (d, 2H, J=9.0 Hz), 7.3-7.6 (m, 6H), 7.0-7.2 (m,2H), 4.2(m,3H), 4.0 (dd, 1H, (J=6.0 Hz, 10.0 Hz), 3.6 (dd, 1H, (J=6.0 Hz,10.0Hz), 3.0 (d, 2H, J=8.0 Hz), 2.0 (m, 1H), 1.6 (m,H) 1.1-1.3 (m, 8H). MassSpec M+H calc 473.1, found 473.

EXAMPLE 195

EXAMPLE 196

EXAMPLE 197

To a stirred solution of the acetic acid salt of (R)-3-aminobutyric acidmethyl ester (8.9 g; 50 mmol) and triethylamine (Et₃N) (21 mL; 150 mmol)in dry methylene chloride (CH₂Cl₂) under N₂ at room temperature is addeddi-tert-butyl dicarbonate (BOC₂O) (21.8 g; 100 mmol) dropwise.4-Dimethylaminopyridine (DMAP) (ca. 50 mg) is then added and the mixtureis allowed to stir at room temperature overnight. At this point, themixture is washed with saturated sodium bicarbonate (NaHCO₃) solution.The organic layer is dried over sodium sulfate (Na₂SO₄), filtered andconcentrated. The crude product is chromatographed (eluent=20% -40%ethyl acetate (EtOAc, or EtOAc) in hexanes) to give Compound 197. ¹H NMR(CDCl₃, δ): 4.92 (bs, 1H), 3.96 (bm, 1H), 3.65 (s, 3H), 2.45-2.37 (m,2H), 1.39 (s, 9H), 1.16 (d, J=7.9 Hz, 3H).

EXAMPLE 198

To a stirred solution of Compound 197 (2.00 g; 9.21 mmol) in 50 mL ofdry tetrahydrofuran (THF) under nitrogen at −78° C. is added lithiumhexamethyldisilazane (LHMDS) solution (25.8 mL of 1.0 M solution in THF)dropwise. The mixture is then warmed up to −20 to −25° C. for 30 min andthen cooled back to −78° C. A solution of 3-cyanobenzyl bromide (4.51 g;23.0 mmol) in dry THF is then added dropwise and the resulting solutionallowed to warm to room temperature. After 1 hour at room temperature,the mixture is quenched with saturated NaHCO₃ solution and most of theTHF is removed in vacuo. The residue is taken up into CH₂Cl₂ and washedwith water. The organic layer is dried (Na₂SO₄), filtered andconcentrated. The crude product is purified by flash chromatography(eluent=25% ethyl acetate/Hexanes). The semi-solid residue is thentriturated with 20% EtOAc/Hexanes and the white solid filtered off. Thefiltrate is then concentrated in vacuo to give Compound 198. ¹H NMR(CDCl₃, δ): 7.25-7.50 (m, 4H), 5.21 (bd, 1H), 3.88 (m, 1H), 3.60 (s,3H), 3.07-2.73 (m, 3H), 1.48 (s, 9H), 1.14 (d, J=7.9 Hz, 3H).

EXAMPLE 199

To a stirred solution of Compound 198 (4.20 g; 12.7 mmol) in 10 mL ofCH₂Cl₂ under N₂ at room temperature is added 20 mL of trifluoroaceticacid. The mixture is allowed to stir overnight at room temperature andthen concentrated in vacuo to give 4.20 g of Compound 199 as thetrifluoroacetic acid (TFA) salt. ¹H NMR (DMSO-d₆, δ): 8.07 (bs, 1H),7.73-7.43 (M, 4H), 3.50 (S, 3H), 3.51 (M, 1H), 3.05-2.82 (M, 3H), 1.23(D, J=7.9 HZ, 3H).

Alternatively, compound 4 may be prepared as outlined below:

EXAMPLE 200

To a stirred solution of D-3-aminobutyric acid methyl ester (6.98 g;39.4 mmol) acetic acid salt in 40 mL of CH₂Cl₂ is added sat. NaHCO₃solution (40 mL). Benzyl chloroformate (9.0 mL; 63 mmol) is then addeddropwise and the mixture allowed to stir vigorously at room temperature.After 3 hours, the organic layer is separated and washed with water. Theorganic layer is dried (Na₂SO₄), filtered and concentrated. The crudeproduct is chromatographed (eluent=10% EtOAc/CHCl₃) to give Compound200. ¹H NMR (CDCl₃, δ): 7.40-7.22 (m, 5H), 5.25 (m, 1H), 5.08 (s, 2H),4.11 (m, 1H), 3.65 (s, 3H), 2.53 (d, J=7.0 Hz, 2H), 1.23 (d, J=7.9 Hz,3H).

EXAMPLE 201

To a stirred solution of Compound 200 (3.45 g; 13.71 mmol) in 20 mL ofdry THF under N₂ at −78° C. is added LHMDS solution (41.2 mL of 1.0 Msolution) dropwise. The mixture is then warmed up to −20° C. for 30minutes and then cooled back to −78° C. A solution of 3-cyanobenzylbromide (4.51 g; 23.0 mmol) in dry THF is then added dropwise and theresulting solution allowed to warm to room temperature. After 1 hour atroom temperature, the mixture is quenched with saturated NaHCO₃ solutionand most of the THF is removed in vacuo. The residue is taken up intoCH₂Cl₂ and washed with water. The organic layer is dried (Na₂SO₄),filtered and concentrated. The crude product is purified by flashchromatography (eluent=30% EtOAc/Hexanes). The semi-solid residue isthen triturated with 20% EtOAc/Hexanes and the white solid filtered off.The semi-solid residue is then triturated with Compound 201. ¹H NMR(CDCl₃, δ) 7.20-7.65 (m, 9H), 5.57 (bd, 1H), 5.12 (s, 2H), 3.97 (m, 1H),3.60 (s, 3H), 3.07-2.75 (m, 3H), 1.16 (d, J=7.9 Hz, 3H).

EXAMPLE 202

To a stirred solution of Compound 201 (2.6 g; 7.1 mmol) in 25 mL ofethanol (EtOH) is added 520 mg of 10% Pd/C. The mixture is stirred under1 atm of hydrogen for 3 hours at room temperature. The mixture is thenfiltered through a bed of celite to remove the catalyst. The filtrate isthen concentrated in vacuo to give 1.45 g of Compound 201.

EXAMPLE 203

3′-pyridyl-4-phenyl carbonyl chloride (Compound 228, prepared as inExample 228) (384 mg; 1.8 mmol) is added in one portion to a solution ofCompound 199 TFA salt (373 mg; 1.6 mmol) and Et₃N (0.67 mL; 4.8 mmol) in5.0 mL of absolute EtOH under N₂ at room temperature. The mixture isallowed to stir overnight at room temperature. The solvent is thenremoved in vacuo and the crude product is purified by chromatography onsilica gel (eluent=70% EtOAc/Hexanes) to provide Compound 203. ¹H NMR(CDCl₃, δ): 8.88 (m, 1H), 8.63 (m, 1H), 7.85-8.00 (m, 7.70 (m, 2H),7.57-7.33 (m, 6H), 4.51 (m, 1H), 3.65 (s, 3H), 3.10-2.82 (m, 3H), 1.28(d, J=7.9 Hz, 3H).

EXAMPLE 204

Acylation of Compound 199 according to the procedure of Example 203,substituting Compound 228 with 4′-pyridyl-4-phenylcarbonyl chloride(Compound 231, prepared as in Example 231) provides, after workup andchromatography, Compound 204. ¹H NMR (CDCl₃, δ): 8.70 (m, 2H), 8.02-7.65(m, 4H), 7.57-7.32 (m, 7H), 4.50 (m, 1H), 3.68 (s, 3H), 3.10-2.83 (M,3H), 1.30 (d, J=7.9 Hz, 3H).

EXAMPLE 205

Acylation of Compound 199 according to Example 203, in CH₂Cl₂ ratherthan absolute EtOH, and substituting 3′-pyridyl-4-phenylcarbonylchloride with 4-biphenylcarbonyl chloride provides, after workup andchromatography, Compound 205. ¹H NMR (CDCl₃, δ): 7.93 (m, 2H), 7.73-7.30(m, 12H), 4.50 (m, 1H), 3.66 (s, 3H), 3.10-2.83 (m, 3H), 1.26 (d, J=7.9Hz, 3H).

EXAMPLE 206

Acylation of Compound 199 according to Example 203 substituting3′-pyridyl-4-phenylcarbonyl chloride with 2-biphenylenecarbonyl chlorideprovides, after workup and chromatography, Compound 206. ¹H NMR (CDCl₃,δ): 7.55-7.27 (m, 5H), 7.07 (m, 2H), 6.85-6.66 (m, 5H), 4.44 (m, 1H),3.65 (s, 3H), 3.05-2.80 (m, 3H), 1.23 (d, J=7.9 Hz, 3H).

EXAMPLE 207

m-Chloroperbenzoic acid (mCPBA) (381 mg; 2.21 mmol) is added to asolution of Compound 204 (608 mg; 1.47 mmol) in 10 mL of CH₂Cl₂ under N₂at room temperature. The resulting mixture allowed to stir overnight atroom temperature. At this point, the mixture is diluted with CH₂Cl₂ andwashed with 5% Na₂CO₃ solution. The organic layer is dried (Na₂SO₄),filtered and concentrated to give Compound 207. MS: M⁺·+H⁺(Calc.)=430;Found (FAB)=430.

EXAMPLE 208

m-Chloroperbenzoic acid (124 mg; 0.72 mmol) is added to a solution ofCompound 203 (150 mg; 0.36 mmol) in 10 mL of CH₂Cl₂ under N₂ at roomtemperature. The resulting mixture is allowed to stir overnight at roomtemperature. At this point, the mixture is diluted with CH₂Cl₂ andwashed with 5% Na₂CO₃ solution. The organic layer is dried (Na₂SO₄),filtered and concentrated to give Compound 208. ¹H NMR (CDCl₃, δ): 8.57(m, 1H), 8.30 (m, 1H), 7.95 (m, 2H), 7.73-7.35 (m, 9H), 4.50 (m, 1H),3.68 (s, 3H), 3.07-2.85 (m, 3H), 1.20 (d, J=7.9 Hz, 3H).

EXAMPLE 209

Hydrogen chloride gas (HCl(g)) is bubbled into a solution of Compound207 (480 mg) in 5.0 mL of dry methanol (MeOH) containing 3 Å molecularsieves (pellets, ca. 50 mg) for about 2 minutes at room temperature. Themixture is allowed to stir overnight at room temperature and thenconcentrated in vacuo. A solution of ammonia (NH₃) in MeOH (5.0 mL of 7Nsolution) is added and the mixture refluxed for 1 hour. The solvent isthen removed in vacuo and the crude product purified by RPHPLC(CH₃CN/H₂O, 0.1% TFA, gradient:10% to 100% CH₃CN and the fractionscontaining product are lyophilized to give Compound 209. ¹H NMR(MeOH-d₄,δ): 8.42 (m, 2H), 8.00-7.85 (m, 6H), 7.68-7.47 (m, 4H), 4.47(m, 1H), 3.60 (s, 3H), 3.18-3.00 (m, 3H), 1.33 (d, J=7.9 Hz, 3H). MS:M⁺·+H⁺(Calc.)=447; Found (FAB)=447.

EXAMPLE 210

Treatment of Compound 203 in a similar manner as in Example 209provides, after purification by RPHPLC, Compound 210. ¹H NMR (DMSO-d6,δ): 9.36 (m, 3H), 8.50-8.27 (m, 2H), 8.00-7.80 (m, 3H), 7.80-7.40 (m,4H), 4.40 (m, 1H), 3.49 (s, 3H), 3.13-2.81 (m, 3H), 1.25 (d, J=7.9 Hz,3H). MS: M⁺·+H⁺(Calc.)=431; Found (FAB)=431

EXAMPLE 211

Treatment of Compound 204 in a similar manner as in Example 209provides, after purification by RPHPLC, Compound 211.

EXAMPLE 212

Treatment of Compound 205 in a similar manner as in Example 209 aboveprovides, after purification by RPHPLC, compound 212. ¹H NMR (DMSO-d₆,δ): 9.30 (s, 1H), 9.00 (s, 1H), 8.40 (m, 1H), 8.05-7.40 (m, 12H), 4.46(m, 1H), 3.56 (s, 3H), 3.20-2.97 (m, 3H), 1.28 (d, J=7.9 Hz, 3H). MS:M⁺·+H⁺(Calc.)=430; Found (FAB)=430.

EXAMPLE 213

Treatment of Compound 208 in a similar manner as in Example 209 aboveprovides, after purification by RPHPLC, Compound 213. ¹H NMR (MeOH-d₄,δ): 8.67 (m, 1H), 8.50-8.35 (m, 2H), 8.00-7.78 (m, 5H), 7.72-7.48 (m,5H), 4.47 (m, 1H), 3.60 (s, 3H), 3.16-3.05 (m, 3H), 1.32 (d, J=7.9 Hz,3H). MS: M⁺·+H⁺(Calc.)=447; Found (FAB)=447.

EXAMPLE 214

Hydrogen sulfide gas (H₂S) is bubbled into a solution of Compound 203(498 mg; 1.21 mmol) in 5.0 mL of pyridine and 1.0 mL of Et₃N for ca. 2minutes. The resulting mixture is allowed to stir overnight at roomtemperature and then concentrated to dryness under a stream of N₂. Theresidue is taken up into 5 mL of CH₂Cl₂ and 5 mL of methyl iodide isadded. The mixture is refluxed for 3 hours, allowed to cool to roomtemperature and concentrated in vacuo. The residue is then taken up into5 mL dry MeOH and NH₄OAc (300 mg) is added. The resulting mixture isrefluxed for 3 h and then concentrated in vacuo. The crude product ispurified by RPHPLC (CH₃CN / H₂O, 0.1% TFA, gradient: 10% to 100% CH₃CNand the fractions containing product are lyophilized to give Compound214. ¹H NMR (MeOH-d₄, δ): 9.35 (s, 1H), 8.92 (m, 2H), 8.50 (d, 1H), 8.17(m, 1H), 8.17 (m, 1H), 8.08-7.92 (m, 4H), 7.66-7.50 (m, 4H), 4.50 (s,3H), 4.50 (m, 1H), 3.58 (s, 3H), 3.15-3.02 (m, 3H), 1.34 (d, J=7.9 Hz,3H). MS: M⁺·(Calc.)=445 ; Found (FAB)=445.

EXAMPLE 215

Treatment of Compound 204 in a similar manner to that of Compound 203 in

EXAMPLE 218 above provides, after purification by RPHPLC, Compound 214.¹H NMR (DMSO-d₆, δ): 9.05 (m, 1H), 8.55 (m, 3H), 8.20-7.97 (m, 5H),7.65-7.47 (m, 4H), 4.33 (s, 3H), 4.10 (m, 1H), 3.13 (s, 3H), 3.13-2.90(m, 3H), 1.27 (d, J=7.9 Hz, 3H). MS: M⁺·(Calc.)=445; Found (FAB)=445.EXAMPLE 216

Treatment of Compound 206 in a similar manner to that of Compound 203 in

EXAMPLE 214 above provides, after purification by RPHPLC, compound 216.EXAMPLE 217

To a stirred solution of sodium methoxide in MeOH (12.4 mL of 0.5 Msolution) is added hydroxylamine hydrochloride. Once all the soliddissolves, the solution is added to a solution of Compound 207 (530 mg;1.24 mmol) in 5 mL of MeOH at room temperature. The resulting mixture isallowed to stir at room temperature under N₂ overnight. At this point,the solvent is removed in vacuo and the product purified by flashchromatography (eluent=10% MeOH/CH₂Cl₂). The fractions containingproduct are concentrated in vacuo and the residue is then lyophilizedfrom water to give Compound 217. ¹H NMR (CDCl₃, δ): 9.60 (s, 1H),8.60-7.10 (m, 12H), 5.80 (bs, 1H), 4.40 (m, 1H), 4.45 (s, 3H), 3.15-2.80(m, 3H), 1.15 (d, J=7.9 Hz, 3H). MS: M⁺·+H⁺(Calc.)=463; Found (FAB)=463.

EXAMPLE 218

Treatment of Compound 208 in a similar manner to that of Compound 207 inExample 217 above provides, after purification by flash chromatography,compound 218. ¹H NMR (MeOH-d₄, δ): 8.69 (m, 1H), 8.35 (m, 1H), 8.00-7.75(m, 5H), 7.72-7.25 (m, 5H), 4.47 (m, 1H), 3.57 9s, 3H), 3.15-2.95 (m,3H), 1.33 (d, J=7.9 Hz, 3H). MS: M⁺+H⁺·(Calc.)=463;Found (ionspray)=463.

EXAMPLE 219

To a stirred solution of Compound 204 (319 mg; 0.77 mmol) in 4 mL ofMeOH/THF (1/1) is added 1 N NaOH solution (10 mL). The resulting mixtureis allowed to stir for 2 hours at room temperature and then acidifiedwith 12 mL of 1 N HCl solution. The solid product Compound 219 isfiltered off and dried in vacuo. ¹H NMR (CDCl₃, δ): 9.30 (bs, 1H), 8.50(bs, 1H), 8.30-7.80 (m, 6H), 7.65-7.28 (m, 5H), 4.40 (m, 1H), 3.20-2.85(m, 3H), a.33 (d, J=7.9 Hz, 3H).

EXAMPLE 220

Triethylamine (0.11 mL; 0.77 mmol) is added dropwise to a suspension ofCompound 219 in dry CH₂Cl₂ (10 mL) under N₂ at room temperature. After10 minutes, isopropyl chloroformate (0.77 mL 0.77 mmol) is addeddropwise. After 30 minutes, DMAP (31 mg) is added and the mixtureallowed to stir overnight at room temperature. At this point, themixture is diluted with CH₂Cl₂ and washed with 1 N HCl. The organiclayer is dried (Na₂SO₄), filtered and concentrated. The crude product ischromatographed with 40% EtOAc/hexanes followed by 70% EtOAc/hexanes togive Compound 220. MS: M⁺·+H⁺(Calc.)=442 ; Found (Ion spray)=442.

EXAMPLE 221

Treatment of Compound 220 in a similar manner to that of Compound 203 inExample 214 above provides, after purification by RPHPLC, Compound 221.¹H NMR (DMSO-d₆, δ): 9.28 (m, 1H), 9.00 (m, 3H), 8.53 (m, 1H), 8.23-7.92(m, 4H), 7.32 (s, 1H), 7.15 (s, 1H), 7.00 (s, 1H), 4.38 (m, 1H), 4.32(s, 3H), 3.14-2.93 (m, 3H), 1.25 (m, 3H), 0.99 (m, 3H), 0.87 (m, 3H).MS: M⁺·(Calc.)=473 ; Found (FAB)=473.

EXAMPLE 222

Ethyl-4-bromobenzoate (7.0 g; 31 mmol) is dissolved in 100 mL of THF. Tothis solution is added Pd(Ph₃P)₄ (1.0 g; 1.0 mmol), tetrabutylammoniumbromide (592 mg; 1.8 mmol), powdered potassium hydroxide (KOH) (3.4 g;61 mmol) and diethyl-(3-pyridyl)borane (3.0 g). The resulting mixture isrefluxed for 2.5 hours, allowed to cool to room temperature andconcentrated in vacuo. The crude product is taken up into MeOH andchromatographed (eluent=gradient, 50% EtOAc/Hexanes to 70%EtOAc/Hexanes) to give, after solvent evaporation, Compound 222. ¹H NMR(CDCl₃, δ): 8.83 (s, 1H), 8.60 (m, 1H), 8.10 (m, 2H), 7.90-7.30 (m, 3H),4.34 (m, 2H), 1.37 (m, 3H).

EXAMPLE 223

Sodium hydroxide solution (25.5 mL of 1.0N solution) is added dropwiseto a stirred solution of Compound 222 (2.7 g; 12 mmol) in 21 mL of 1/1THF/MeOH at room temperature. After 3 hours, 25 mL of 1N HCl is addedand the white precipitate is filtered off. The solid is dried in vacuo.to give Compound 223. ¹H NMR (DMSO-d₆, δ): 8.90 (s, 1H), 8.60 (s, 1H),8.13 (m, 1H), 8.05-7.80 (m, 4H), 7.50 (m, 1H).

EXAMPLE 224

Thionyl chloride (5 mL) is added to 1.3 g of Compound 223. The resultingmixture is refluxed for 2 hours and then concentrated in vacuo to giveCompound 224. MS: M⁺·(Calc.)=217 ; Found (EI)=217.

EXAMPLE 225

A mixture of methyl coumalate (10 g; 65 mmol), 4-vinylpyridine (35 mL;325 mmol) and 10% Pd/C (25 g) in mesitylene (300 mL) is heated at 200°C. for 30 hours. At this point, the mixture is allowed to cool andfiltered through celite washing with CHCl₃. Most of the solvent is thenremoved in vacuo and the remaining liquid is chromatographed (eluent:Gradient, 50% EtOAc/Hex. to 70% EtOAc/Hex.) to give Compound 225. MS:M⁺·(Calc.)=213; Found (EI)=213.

EXAMPLE 226

Treatment of Compound 225 with sodium hydroxide in THF/MeOH as inExample 227 provides Compound 226. MS: M⁺·(Calc.)=199; Found (EI)=199.

EXAMPLE 227

Treatment of Compound 226 with refluxing thionyl chloride as in Example228 provides Compound 227. MS: M⁺·(Calc.)=217; Found (EI)=217.

EXAMPLE 228

To N-BOC homophenylalanine methylester (5.57 g; 18.1 mmol) in 30 mL ofTHF under N₂ at −78° C. is added LHMDS solution dropwise (54.3 mL of 1Nsolution in THF). The mixture is then allowed to warn up to 0° C. for 30min and then cooled back to −78° C. A solution of 3-cyanobenzyl bromide(7.46 g; 38.0 mmol) in dry THF is then added dropwise and the resultingsolution allowed to warm to room temperature. After 1 hour at roomtemperature, the mixture is quenched with saturated NaHCO₃ solution andmost of the THF is removed in vacuo. The residue is taken up into CH₂Cl₂and washed with water. The organic layer is dried (Na₂SO₄), filtered andconcentrated. The crude product is purified by flash chromatography(eluent=25% EtOAc/Hexanes. The semi-solid residue is then trituratedwith 20% EtOAc/Hexanes and the white solid filtered off. The filtrate isthen concentrated in vacuo to Compound 228. ¹H NMR (CDCl₃, δ): 7.82-7.08((m, 9H), 5.32 (bd, 1H), 3.84 (m, 1H), 3.60 (s, 3H), 3.06-2.57 (m, 5H),1.70 (m, 2H), 1.47 (s, 9H).

EXAMPLE 229

To a stirred solution of Compound 228 (1.42 g; 3.35 mmol) in 5.0 mL ofCH₂Cl₂ under N₂ at 0° C. is added 3.5 mL of trifluoroacetic acid. Themixture is allowed to stir for 2 hours at room temperature and thenconcentrated in vacuo to give Compound 229 as the TFA salt. MS:M⁺·(Calc.)=322; Found (EI)=322.

EXAMPLE 230

Acylation of Compound 229 according to Example 203 with Compound 228provides, after workup and chromatography, Compound 230. MS:M⁺·(Calc.)=503; Found (EI) =503.

EXAMPLE 231

Treatment of Compound 234 with HCl / MeOH, then NH₄OAc in a similarmanner to Compound 207 in Example 209 above provides, after purificationby RPHPLC, Compound 235. MS: M⁺·+H⁺(Calc.)=521; Found (FAB)=521.

EXAMPLE 236

Treatment of Compound 234 in a similar manner to that of Compound 203 in

EXAMPLE 218 above provides, after purification by RPHPLC, Compound 236.¹H NMR (MeOH-d₄): 9.35 (s, 1H), 8.90 (m, 2H), 8.45 (m, 1H), 8.17 (m,1H), 8.11-7.92 (m, 4H), 7.68-7.46 (m, 5H) 7.27-7.10 (m, 6H), 4.50 (s,3H), 4.40 (m, 1H), 3.57 (s, 3H), 3.05 (m, 3H), 2.67 (m, 2H), 2.00 (m,2H). EXAMPLE 237

Hydrolysis of Compound 234 with sodium hydroxide in THF/MeOH using theprocedure of Example 227 provides after workup, Compound 237. MS:M⁺·+H⁺(Calc.)=490; Found (FAB)=490.

EXAMPLE 238

Treatment of Compound 237 in a similar manner to Compound 203 in Example218 above provides, after purification by RPHPLC, Compound 238. ¹H NMR(MeOH-d₄): 9.38 (s, 1H), 8.90 (m, 2H), 8.47 (m, 1H), 8.17 (m, 1H),8.11-7.92 (m, 4H), 7.68-7.46 (m, 5H), 7.26-7.10 (m, 6H), 4.50 (s, 3H),4.38 (m, 1H), 3.12-2.97 (m, 3H), 2.68 (m, 2H), 2.03 (m, 2H). EXAMPLE 239

This material is prepared following the procedure described for compound123 and substituting benzimidazole-5-carboxyic acid for 99.

EXAMPLE 240

This material is prepared following the procedure described for compound123 and substituting quinoline-7-carboxylic acid for 99.

EXAMPLE 241

This material is prepared following the procedure described for compound123 and substituting N-(4-pyridyl)-piperidine-4carboxylic acid for 99.

EXAMPLE 242

This material is prepared following the procedure described for compound123 and substituting 2-(1-piperazinyl)pyridine-5-carboxylic acid for 99.

EXAMPLE 243

This material is prepared following the procedure described for compound123 and substituting 2-(4pyridinyl)-1,3-thiazole-4-carboxylic acid for99.

EXAMPLE 244

This material is prepared following the procedure described for compound123 and substituting 4-(5-(1,2,4-thiadiazolyl))benzoic acid for 99.

EXAMPLE 245

This material is prepared following the procedure described for compound123 and substituting 2-(2-pyridyl)thiophene-5-carboxylic acid for 99.

EXAMPLE 246

This material is prepared following the procedure described for compound123 and substituting 2-(3-pyridyl)thiophene-5-carboxylic acid for 99.

EXAMPLE 247

This material is prepared following the procedure described for compound123 and substituting 2-(4pyridyl)thiophene-5-carboxylic acid for 99.

EXAMPLE 248

This material is prepared following the procedure described for compound123 and substituting 3-(2-pyridyl)thiophene-5-carboxylic acid for 99.

EXAMPLE 249

This material is prepared following the procedure described for compound123 and substituting 3-(3-pyridyl)thiophene-5-carboxylic acid for 99.

EXAMPLE 250

This material is prepared following the procedure described for compound123 and substituting 3-(4-pyridyl)thiophene-5-carboxylic acid for 99.

EXAMPLE 251

This material is prepared following the procedure described for compound123 and substituting 4-(1-imidazolyl)benzoic acid for 99.

EXAMPLE 252

This material is prepared following the procedure described for compound123 and substituting 4-(4-imidazolyl)benzoic acid for 99.

EXAMPLE 253

This material is prepared following the procedure described for compound123 and substituting 4-(2-imidazolyl)benzoic acid for 99.

EXAMPLE 254

This material is prepared following the procedure described for compound123 and substituting 3-(1-imidazolyl)benzoic acid for 99.

EXAMPLE 255

This material is prepared following the procedure described for compound123 and substituting 2-(1-imidazolyl)pyridine-5-carboxylic acid for 99.

EXAMPLE 256

This material is prepared following the procedure described for compound123 and substituting 2-(1-pyrrolyl)pyridine-5-carboxylic acid for 99.

EXAMPLE 257

This material is prepared following the procedure described for compound123 and substituting 4-(1-pyrrolyl)benzoic acid for 99.

EXAMPLE 258

This material is prepared following the procedure described for compound123 and substituting 5-(3-pyridyl)-1,3-thiazole-2-carboxylic acid for99.

EXAMPLE 259

This material is prepared following the procedure described for compound123 and substituting 2-phenyl-5-methyl-1,2,3-triazole-4-carboxylic acidfor 99.

EXAMPLE 260

This material is prepared following the procedure described for compound123 and substituting 2-(2,4-difluorophenyl)-1,3-thiazole-4-carboxylicacid for 99.

EXAMPLE 261

This material is prepared following the procedure described for compound123 and substituting 2-(2,3-dichlorophenyl)-1,3-thiazole-4-carboxylicacid for 99.

EXAMPLE 262

This material is prepared following the procedure described for compound123 and substituting 3-phenyl-5-methyl-1,2-diazole-4-carboxylic acid for99.

EXAMPLE 263

This material is prepared following the procedure described for compound123 and substituting 1,2-phthalimide-4carboxylic acid for 99.

EXAMPLE 264

This material is prepared following the procedure described for compound123 and substituting 3-aza-b-carboline-4-carboxylic acid for 99.

EXAMPLE 265

This material is prepared following tie procedure described for compound123 and substituting 2-methyl-1-azaindolizine-3-carboxylic acid for 99.

EXAMPLE 266

This material is prepared following the procedure described for compound56 and substituting N-a-Boc-O-benzyl-D-serine.

EXAMPLE 267

This material is prepared following the procedure described for compound62 and substituting Compound 266.

EXAMPLE 268

This material is prepared following the procedure described for compound68 and substituting Compound 267.

EXAMPLE 269

This material is prepared following the procedure described for compound114 and substituting Compound 268.

EXAMPLE 270

This material is prepared following the procedure described for compound129 and substituting Compound 269.

EXAMPLE 271

This material is prepared following the procedure described for compound159a and substituting Compound 239. MS: (M+H)⁺395.

EXAMPLE 272

This material is prepared following the procedure described for compound159a and substituting Compound 240. MS: (M+H)⁺406.

EXAMPLE 273

This material is prepared following the procedure described for compound159a and substituting Compound 241. MS: (M+H)⁺439.

EXAMPLE 274

This material is prepared following the procedure described for compound159a and substituting Compound 242. MS: (M+H)⁺440.

EXAMPLE 275

This material is prepared following the procedure described for compound159a and substituting Compound 243. MS: (M+H)⁺439.

EXAMPLE 276

This material is prepared following the procedure described for compound159a and substituting Compound 244. MS: (M+H)⁺439.

EXAMPLE 277

This material is prepared following the procedure described for compound159a and substituting Compound 245. ¹H NMR (DMSO-d₆) δ8.56-8.50 (m, 1H),7.94-7.82 (m, 2H), 7.70 (s, 2H), 7.66-7.46 (m, 4H), 7.38-7.30 (m, 1H),4.46-4.32 (m, 1H), 3.60 (s, 3H), 3.13-2.95 (m, 3H), 1.32 (d, J=7.2 Hz,3H). MS: (M+H)⁺438.

EXAMPLE 278

This material is prepared following the procedure described for compound159a and substituting Compound 246. ¹H NMR (DMSO-d₆) δ9.06 (s, 1H),8.68-8.62 (m, 1H), 8.53 (d, J=8.4 Hz, 1H), 7.85-7.78 (m, 1H), 7.75 (d,J=3.6 Hz, 1H), 7.68 (d, J=3.6 Hz, 1H), 7.65-7.45 (m, 4H), 4.48-4.33 (m,1H), 3.57 (s, 3H), 3.13-3.00 (m, 3H), 1.32 (d, J=7.2 Hz, 3H). MS:(M+H)⁺438.

EXAMPLE 279

This material is prepared following the procedure described for compound159a and substituting Compound 247. ¹H NMR (DMSO-d₆) δ8.70 (s, 1H), 8.52(d, J=9.6 Hz, 1H), 8.18-8.08 (m, 1H), 7.96 (d, J=3.6 Hz, 1H), 7.82 (d,J=3.6 Hz, 1H), 7.65-7.45 (m, 4H), 4.50-4.35 (m, 1H), 3.57 (s, 3H),3.13-3.02 (m, 3H), 1.34 (d, J=7.2 Hz, 3H). MS: (M+H)⁺438.

EXAMPLE 280

This material is prepared following the procedure described for compound159a and substituting Compound 248. ¹H NMR (DMSO-d₆) δ8.66 (d, J=6.0 Hz,1H), 8.37 (s, 1H), 8.32 (s, 1H), 8.20-8.11 (m, 1H), 8.04 (d, J=7.2 Hz,1H), 7.65-7.44 (m, 5H), 4.50-4.35 (m, 1H), 3.60 (s, 3H), 3.17-3.02 (m,3H), 1.33 (d, J=7.2 Hz, 3H). MS: (M+H)⁺438.

EXAMPLE 281

This material is prepared following the procedure described for compound159a and substituting Compound 249. ¹H NMR (DMSO-d₆) δ9.15-9.02 (m, 1H),8.75-8.61 (m, 1H), 8.54 (d, J=8.4 Hz, 1H), 8.22 (d, J=8.4 Hz, 1H),7.88-7.78 (m, 1H), 7.65-7.45 (m, 4H), 4.50-4.35 (m, 1H), 3.57 (s, 3H),3.17-3.02 (m, 3H), 1.35 (d, J=7.2 Hz, 3H). MS: (M+H)⁺438.

EXAMPLE 282

This material is prepared following the procedure described for compound159a and substituting Compound 250. ¹H NH NMR (DMSO-d₆) δ8.78 (s, 2H),8.67 (s, 1H), 8.35 (s, 1H), 8.25 (d, J=8.4 Hz, 2H), 7.65-7.45 (m, 4H),4.50-4.38 (m, 1H), 3.57(s, 3H), 3.17-3.02 (m, 3H), 1.35 (d, J=7.2 Hz,3H). MS: (M+H)⁺438.

EXAMPLE 283

This material is prepared following the procedure described for compound159a and substituting Compound 251. ¹H NMR (DMSO-d₆) δ9.5 (s, 1H), 8.2(s, 1H), 8.1 (d, J=5.0 Hz, 2H), 7.9 (d, J=5.0 Hz, 2H, 7.8 (s, 1H),7.5-7.7 (m, 4H), 4.4-4.6 (m, 1H), 3.6 (s, 3H), 3.03-3.02 (m, 3H), 1.4(d,J=5.0 Hz, 3H). MS: (M+H)⁺421.

EXAMPLE 284

This material is prepared following the procedure described for compound159a and substituting Compound 252. ¹H NMR (DMSO-d₆) δ9.0 (s, 1H), 8.5(d, J=5.0 Hz, 1H), 8.1 (s, 1H), 8.0 (d, J=5.0 Hz, 2H), 7.9 (d, J=5.0 Hz,2H), 7.5-7.7 (m, 4H), 4.4-4.6 (m, 1H), 3.6 (s, 3H), 3.0-3.2 (m, 3H), 1.4(d, J=5.0 Hz, 3H). MS: (M+H)⁺421.

EXAMPLE 285

This material is prepared following the procedure described for compound159a and substituting Compound 253. ¹H NMR (DMSO-d₆) δ8.5 (d, J=5.0 Hz,1H), 7.80-8.10 (m, 4H), 7.8 (d, J=5.0 Hz, 2H), 7.5-7.7 (m, 4H), 4.4-4.6(m, 1H), 3.6 (s, 3H), 3.0-3.1 (m, 3H), 1.4 (d, J=5.0 Hz, 3H). MS:(M+H)⁺421.

EXAMPLE 286

This material is prepared following the procedure described for compound159a and substituting Compound 254. MS: (M+H)⁺421.

EXAMPLE 287

This material is prepared following the procedure described for compound159a and substituting Compound 255. MS: (M+H)⁺422.

EXAMPLE 288

This material is prepared following the procedure described for compound159a and substituting Compound 256. MS: (M+H)⁺421.

EXAMPLE 289

This material is prepared following the procedure described for compound159a and substituting Compound 257. MS: (M+H)⁺420.

EXAMPLE 290

This material is prepared following the procedure described for compound159a and substituting Compound 258. MS: (M+H)⁺439.

EXAMPLE 291

This material is prepared following the procedure described for compound159a and substituting Compound 259. MS: (M+H)⁺436.

EXAMPLE 292

This material is prepared following the procedure described for compound159a and substituting Compound 260. MS: (M+H)⁺473.

EXAMPLE 293

This material is prepared following the procedure described for compound159a and substituting Compound 261. MS: (M+H)⁺507.

EXAMPLE 294

This material is prepared following the procedure described for compound159a and substituting Compound 262. MS: (M+H)⁺434.

EXAMPLE 295

This material is prepared following the procedure described for compound159a and substituting Compound 263. MS: (M+H)⁺421.

EXAMPLE 296

This material is prepared following the procedure described for compound159a and substituting Compound 264. MS: (M+H)⁺444.

EXAMPLE 297

This material is prepared following the procedure described for compound159a and substituting Compound 265. MS: (M+H)⁺408.

EXAMPLE 298

This material is prepared following the procedure described for compound159b and substituting Compound 269.

EXAMPLE 299

This material is prepared following the procedure described for compound159b and substituting Compound 270.

EXAMPLE 300

To a solution of compound 298 (1 mmol) in 20 mL of CH₂Cl₂ is added 5 mLof TFA at 0° C. with stirring. Stirring is continued for 1 hour at 0° C.and all solvents are removed in vacuo.

EXAMPLE 301

To a solution of compound 300 (1 mmol) in 25 mL of methanol is addedapproximately 50 mg of 10% palladium on charcoal. The mixture is shakenunder a positive pressure of hydrogen (55 psi) for 24 hours andfiltered. The filtrate is concentrated in vacuo and purified by reversephase HPLC. ¹H NMR (DMSO-d₆) δ8.3 (d, J=6.0 Hz, 1H), 8.0 (d, J=5.0 Hz,2H), 7.8 (d, J=5.0 Hz 2H), 7.7 (d, J=6.0 Hz, 2H), 7.4-7.7 (m, 6H),4.3-4.5 (m, 1H), 4.2 (s, 2H), 3.8 (d, J=4.0 Hz, 2H), 3.7 (s, 3H),3.2-3.4 (m, 3H), 3.1-3.2 (m, 2H). MS: (M+H)⁺475.

EXAMPLE 302

Compound 302 is prepared in a manner identical to compound 300, startingfrom compound 299.

EXAMPLE 303

Compound 303 is prepared in a manner identical to compound 301, startingfrom compound 302. ¹H NMR (DMSO-d₆) δ8.4 (d, J=5.0 Hz, 1H), 8.0 (d,J=5.0 Hz, 2H), 7.8 (d, J=5.0 Hz, 2H), 7.7 (d, J=4.0 Hz, 2H), 7.5-7.7 (m,6H), 4.2 (s, 2H), 4.1-4.2 (m, 1H), 4.0 (dd, J=8.0, 2.0 Hz, 1H), 3.8 (s,2H), 3.7 (dd, J=8.0 Hz, 1H), 3.0 (d, J=5.0 Hz, 2H), 2.2-2.4 (m, H), MS:(M+H)⁺448.

EXAMPLE 304

Compound 304 is prepared by procedures substantially similar to thoseused to prepare compound 301, starting from the appropriate materials.¹H NMR (CD₃OD) δ7.94 (d, J=10.8 Hz, 2H), 7.85-7.72 (m, 4H), 7.70-7.45(m, 6H), 4.32-4.23 (m, 1H), 4.22 (s, 2H), 3.62 (s, 3H), 3.83-3.55 (m,2H), 3.18-3.02 (m, 3H), 0.94 (t, J=8.4 Hz, 3H). MS: (M+H)⁺474.

EXAMPLE 305

Compound 305 is prepared by procedures substantially similar to thoseused to prepare compound 301, starting from the appropriate materials.¹H NMR (CD₃OD) δ7.94 (d, J=10.8 Hz, 2H), 7.85-7.72 (m, 4H), 7.68-7.45(m, 6H), 4.42-4.30 (m, 1H), 4.22 (s, 2H), 3.61 (s, 3H), 3.15-3.02 (m,3h), 1.72-1.58 (m, 2H), 1.51-1.32 (m, 2H), 0.93 (t, J=8.4 Hz, 3H). MS:(M+H)⁺488.

EXAMPLE 306

Compound 306 is prepared by procedures substantially similar to thoseused to prepare compound 301, starting from the appropriate materials.¹H NMR (CD₃OD) δ7.93 (d, J=10.8 Hz, 2H), 7.85-7.72 (m, 4H), 7.70-7.45(m, 6H), 4.42-4.30 (m, 1H), 4.22 (s, 2H), 3.62 (s, 3H), 3.14-3.02 (m,3H), 1.78-1.60 (m, 2H), 1.45-1.25 (m, 4H), 0.90 (t, J=8.4 Hz, 3H). MS:(M+H)⁺502.

EXAMPLE 307

Compound 307

(Z)-N-[3-(5-Carbamimidoyl-2-hydroxyphenyl)allyl]-4-pyridin-3-ylbenzamide

A. 5-Iodo-2-(2-methoxyethoxymethoxy)benzaldehyde

A 1 M solution of Iodine monochloride in dichloromethane (410 mL, 0.41mol) is added to a solution of salicylaldehyde (50 g, 0.41 mol) indichloromethane (150 mL) at 0° C. The resulting solution is warmed toroom temperature and stirred overnight. The deep colored solution isdischarged with saturated aqueous Na₂SO₃ (100 mL). The organic layer isseparated, washed with water, dried over MgSO₄, filtered andconcentrated. The crude product is recrystallized from cyclohexane togive 4-iodosalicylaldehyde as yellow crystals (61 g, 0.25 mol). Asolution of 4-iodosalicylaldehyde (12.4 g, 50 mmol) and MEM chloride (6mL, 53 mmol) in THF (50 mL) is added to a suspension of 60% NaH (2.2 g,55 mmol) in THF (50 mL) at 0° C. The resulting mixture is stirred atroom temperature for 2 hours. Aqueous workup and concentration givesproduct as a liquid (15 g, 45 mmol). ¹H NMR (CDCl₃, 300 MHz) δ10.36 (s,1H), 8.11 (d, 1H), 7.73 (dd, 1H), 7.03 (d, 1H), 5.37 (s, 2H), 3.88 (t,2H), 3.52 (t, 2H), 3.36 (s, 3H). EI MS [M]⁺=436.

B. (Z,E)-3-[3-(1,3-Dioxo-1,3-diydroisoindol-2-yl)propenyl]-4-(2-methoxy-ethoxymethoxy)benzonitrile

Potassium t-butoxide (1.85 g, 16,5 mmol) is added to a suspension of5-iodo-2-(2-methoxy-ethoxymethoxy)benzaldehyde (5 g, 15 mmol) and[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)ethyl]-triphenyl-phosphoniumbromide (7.7 g, 15 mmol) in THF (80 mL). The mixture is stirred at roomtemperature overnight. the precipitated solid is removed, the filtrateis concentrated, diluted with water and extracted twice with CHCl₃. Thecombined organic layers are washed with water, dried over MgSO₄,filtered and concentrated. The crude product is purified bychromatography (10% to 30% EtOAc/hexanes) to give a yellow solid (3.1 g,6.3 mmol). This product (2.5 g, 5.1 mmol) is mixed with ZnCN₂ (2.1 g,17.5 mmol) and (Ph₃P)₄Pd (0.3 g, 0.26 mmol) in DMF (15 mL). The mixtureis heated at 75° C. for 4 hours, then cooled, diluted with EtOAc, washedwith 5% NH₄OH, water and brine (5×25 mL), dried over MgSO₄, filtered andconcentrated. The crude product is purified by flash chromatography (15%to 30% EtOAc/hexanes) to give a mixture of two isomers (Z/E=4/1) as awhite solid (1.0 g, 26 mmol). Fab MS [M+1]⁺=393.

C. (Z)-3-(3-Aminopropenyl)-4-(2-methoxy-etboxymethoxy)benzonitrile

(Z,E)-3-[3-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)propenyl]-4-(2-methoxyethoxy-methoxy)benzonitrile(0.2 g, 0.51 mmol) and NH₂NH₂ hydrate (0.15 mL, 3 mmol) in 1-butanol (10mL) is heated to 90° C. for 1 hour. The reaction is cooled and theresulting suspension is filtered. The filtrate is concentrated to aresidue which is purified by chromatography (15% to 20% EtOH/CH₂Cl₂).The high Rf material is identified as the Z-isomer (30 mg, 0.11 mmol).¹H NMR (CDCl₃, 300 MHz) δ7.55 (dd, 1H), 7.45 (d, 1H), 7.20 (d, 1H), 6.50(d, 1H), 5.9 (m, 1H), 5.37 (s, 2H), 3.80 (t, 2H), 3.50 (m, 4H), 3.30 (s,3H). EI MS [M]⁺=262.

D.(Z)-N-[3-(5-Carbamimidoyl-2-hydroxyphenyl)-allyl]-4-pyridin-3-yl-benzamide

(Z)-3-(3-Aminopropenyl)-4-(2-methoxy-ethoxymetboxy)benzonitrile (30 mg,0.11 mmol) in DMF (2 mL) is added to the mixture of 4-pyridin-3-ylbenzoic acid (24 mg, 0.12 mmol), TBTU (39 mg, 0.12 mmol), and Et₃N (12mg, 0.12 mmol) in DMF (0.5 mL), and stirred at room temperatureovernight. The solution is diluted with water and extracted with CH₂Cl₂(3X). The combined CH₂Cl₂ layers are washed with water, dried overMgSO₄, filtered and concentrated. The crude product is purified bychromatography in a gradient of 2% MeOH/CH₂Cl₂ to give a white solid (35mg, 0.079 mmol). The above product is treated with HCl gas in EtOH (9mL) for 20 min, then sealed and stirred overnight. After concentratingto dryness, the product is treated with a saturated solution of NH₃ gasin MeOH (10 mL) at 50° C. for 2 hours. The reaction is sealed andstirred at room temperature overnight. White solid is collected andwashed with MeOH. More product is obtained from the filtrate afterconcentrating to a small volume (26 mg combined, 0.07 mmol). ¹H NMR(DMSO, 300 MHz) δ9.05 (bs, 1H), 8.95 (s, 1H), 8.60 (s, 1H), 8.15 (d,1H), 7.97 (d, 2H), 7.84 (d, 2H), 7.50 (m, 2H), 7.40 (d, 1H), 6.20 (d,1H), 5.50 (m, 1H), 4.17 (bs, 2H). Ion spray MS [M+1]+=373, [M+2]=187.

EXAMPLE 308

Compound 308

N-[3-(5-Carbamimidoyl-2-hydroxyphenyl)-propyl]-4-pyridin-3-yl)-benzamideditrifluoroacetate

(Z)-N-[3-(5-Carbamimidoyl-2-hydroxyphenyl)-allyl]-4-pyridin-3-yl-benzamide(22 mg, 0.059 mmol) is dissolved in MeOH (10 mL) and hydrogenated at 30psi H₂ for 2 hours in the present of 5% Pd/C. The mixture is filtered,washed with MeOH, and concentrated. The product is purified by HPLCeluting with a gradient of 10% MeCN/H₂O (0.1% TFA) to 100% MeCN.Lyophylization of the appropriate fraction gives the title compound as awhite solid (35 mg, 0.056 mmol). ¹H NMR (DMSO, 300 MHz) δ10.6 (bs, 1H),8.97 (bs, 2H), 8.70 (m, 3H), 8.20 (d, 1H), 7.90 (d, 2H), 7.80 (d, 2H),7.55 (m, 3H), 6.90 (d, 1H), 3.25 (t, 2H), 2.60 (t, 2H), 1.78 (m, 2H).Ion spray MS [M+1]+=375, [M+2]²⁺=188.

EXAMPLE 309

Compound 309

N-[3-(5-Carbamimidoyl-2-hydroxyphenyl)-propyl]-4-(1-oxy-pyridin-4-yl)-benzamideditrifluoroacetate

A. 3-(3-Aminopropyl)-4-(2-methoxy-ethoxymethoxy)benzonitrile

(Z,E)-3-[3-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)propenyl]-4-(2-methoxy-ethoxymethoxy)benzonitrile(0.38 g, 0.97 mmol) in 50% MeOH/CH₂Cl₂ (10 mL) is hydrogenated (H₂filled balloon) overnight in the presence of 5% Pd/C. The mixture isfiltered, washed with CH₂Cl₂, and concentrated. The above residue andNH₂NH₂ hydrate (0.23 mL, 4.6 mmol) in 1-butanol (15 mL) is heated to 90°C. for 1 hour. After cooling, the solid is removed by filtration, andwashed with 1-butanol. The filtrate is concentrated to give the titlecompound as a light yellow solid (0.23 g, 0.87 mmol). ¹H NMR (CDCl₃, 300MHz) δ7.45 (m, 2H), 7.17 (d, 1H), 5.34 (s, 2H), 3.82 (t, 2H), 3.55 (t,2H), 3.38 (s, 3H), 2.70 (m, 4H), 1.70 (m, 2H).

B.N-[3-(5-Carbamimidoyl-2-hydroxy-phenyl)-propyl]-4-(1-oxy-pyridin-4-yl)-benzamideditrifluoroacetate

3-(3-Aminopropyl)-4-(2-methoxyethoxymethoxy)benzonitrile (88 mg, 0.33mmol) in DMF (0.5 mL) is added to a mixture of 4-pyridin-4-yl benzoicacid (60 mg, 0.3 mmol), TBTU (106 mg, 0.33 mmol), and Et₃N (0.043 mL,0.033 mmol) in DMF (1 mL). The mixture is stirred at 35° C. for 4 hours.The solution is diluted with EtOAc (20 mL), washed with saturated NaHCO₃(3×17 mL) and brine (3×17 mL), dried over MgSO₄, filtered andconcentrated. The residue is chromatographed (4% MeOH/CH₂Cl₂) to give3-[4-(pyridin-4-yl)-benzamido]propyl)-4-(2-methoxyethoxymethoxy)-benzonitrile(0.09 g, 0.20 mmol), contaminated with an unknown byproduct. The crudematerial (0.08 g, 0.18 mmol) is dissolved in CH₂Cl₂ (5 mL), treated withMCPBA (57-86%, 92 mg) at 0° C., a room temperature for 2 hours. Theresidue from aqueous workup and concentration is treated with anhydrousHCl/EtOH followed by ammonolysis as described in Example 307, part D.HPLC purification (10% MeCN/0.1% TFA in H₂O to 100% MeCN) gave the titlecompound (0.007 g, 0.01 mmol). ¹H NMR (CD₃OD, 300 MHz) δ8.94 (bs, 1H),8.65 (bs, 1H), 8.40 (m, 3H), 7.90 (m, 6H), 7.64 (d, 1H), 7.57 (dd, 1H),6.93 (d, 1H), 3.43 (t, 2H), 2.77 (t, 2H), 1.97 (m, 2H). Ion spray MS[M+1]=391, [M+2]²⁺=196.

EXAMPLE 310

Compound 310

N-[3-(5-Carbamimidoyl-2-hydroxyphenyl)-propyl]-4-(6-oxo-1,6-dihydropyridin-3-yl-benzamidetrifluroacetate

A.3-[4-(6-oxo-1,6-dihydropyridin-3-yl)-benzamido]propyl)-4-hydroxybenzonitrile

3-(3-Aminopropyl)-4-(2-methoxyethoxymethyl)benzonitrile (0.048 g, 0.18mmol) is treated with 4-(6-methoxypyridin-3-yl)benzoic acid (0.042 g,0.18 mmol), TBTU (0.058, 0.18 mmol), and triethylamine (0.025 mL), asdescribed in EXAMPLE 309, part B to give, after chromatography (CH₂Cl₂to 5% MeOH/CH₂Cl₂),3-[4-(6-methoxypyridin-3-yl)-benzamido]propyl)-4-(2-methoxyethoxymethoxy)-benzonitrile.This material is heated with pyridinium hydrochloride to a melt for 15minutes. The reaction mixture is cooled and diluted with water (20 mL);the precipitated product,3-{3-[4-(6-methoxypyridin-3-yl)-benzamido]propyl}-4-hydroxybenzonitrileis collected by filtration (0.031 g, 0.083 mmol). ¹H NMR (CD₃OD, 300MHz) δ8.1 (m, 1H), 7.97 (m, 1H), 7.90 (AB, 2H), 7.76 (bs, 1H), 7.60 (AB,2H), 7.95 (s, 1H), 7.40 (d, 1H), 6.93 (d, 1H), 6.87 (d, 1H), 6.67 (d,1H), 3.45 (t, 2H), 2.73 (t, 2H), 1.93 (m, 2H). Ion spray MS [M+1]⁺=374.

B.N-[3-(5-Carbamimidoyl-2-hydroxyphenyl)-propyl]-4-(6-oxo-1,6-dihydropyridin-3-yl-benzamidetrifluroacetate

3-{3-[4-(6-methoxypyridin-3-yl)-benzamido]propyl}-4-hydroxybenzonitrileis converted to the title compound by anhydrous HCl/EtOH followed byammonolysis as described in Example 307, part D. HPLC purification (10%MeCN/0.1% TFA in H₂O to 100% MeCN) yielded the title compound (0.018 g,0.046 mmol). ¹H NMR (CD₃OD, 300 MHz) δ8.94 (bs, 1H), 8.53 (bs, 1H), 8.0(dd, 1H), 7.92 (AB, 2H), 7.84 (s, 1H), 7.65 (m, 3H), 7.56 (dd, 1H), 6.95(d, 1H), 6.67(d, 1H), 3.42 (t, 2H), 2.77 (t, 2H), 1.98 (m, 2H). Ionspray MS [M+1]⁺=391.

EXAMPLE 311

Compound 311

N-[3-(5-Carbamimidoyl-2-hydroxyphenyl)-propyl]-4-(pyridazin-4-yl)benzamideditrifluoroacetate

A.3-{3-[4-(Pyridazin-4-yl)benzamido]propyl}-4-(2-methoxyethoxymethoxy)-benzonitrile

3-(3-Aminopropyl)-4-(2-methoxyethoxymethyl)benzonitrile (0.05 g, 0.19mmol) is treated with 4-(pyridazin-4-yl)benzoic acid (0.038 g, 0.18mmol), TBTU (0.058 g, 0.18 mmol), and triethylamine (0.035 mL), asdescribed in EXAMPLE 309, part B to give, after chromatography (CH₂Cl₂to 5% MeOH/CH₂Cl₂), the title compound. (0.045 g, 0.10 mmol). ¹H NMR(CDCl₃, 300 MHz) δ9.47 (d, 1H), 9.27 (d, 1H), 7.97 (AB, 2H), 7.63 (AB,2H), 7.69 (dd, 1H), 7.46 (s, 1H), 7.18 (d, 1H), 6.69 (d, 1H), 5.37 (s,2H), 3.82 (m, 2H), 3.50 (m, 4H), 3.35 (s, 3H), 2.73 (t, 2H), 1.97 (m,2H) Ion Spray MS, [M+H]⁺=447.

B.N-[3-(5-Carbamimidoyl-2-hydroxyphenyl)-propyl]-4-(pyridazin-4-yl)benzamideditrifluroacetate

b3-{3-[4-(Pyridazin-4-yl)benzamido]propyl}-4-(2-methoxyethoxymethoxy)-benzonitrile(0.045 g, 0.10 mmol) is converted to the title compound by anhydrousHCl/EtOH treatment followed by ammonolysis as described in EXAMPLE 307,part D. HPLC purification gave the title compound (0.025 g, 0.066 mmol).¹H NMR (DMSO, 300 MHz) δ10.65 (s, 1H), 9.70 (s, 1H), 9.30 (s, 1H), 9.0(bs, 2H), 8.71 (m, 3H), 8.05 (m, 5H), 7.63 (s, 1H), 7.55 (dd, 1H), 6.95(d, 1H), 3.3 (m, 2H), 2.64 (t, 2H), 1.85 (m, 2H). Ion spray MS[M+1]⁺=376.

EXAMPLE 312

Compound 312

N-[3-(5-Carbamimidoyl-2-hydroxyphenyl)-propyl]-7-chlorobenzothiophene-2-carboxamidetrifluroacetate

3-(3-Aminopropyl)-4-(2-methoxyethoxymethyl)benzonitrile (0.05 g, 0.19mmol) is treated with 7-chlorobenzothiophene-2-carboxylic acid (0.044 g,0.020 mmol), TBTU (0.058, 0.18 mmol), and triethylamine (0.025 mL), asdescribed in EXAMPLE 309, part B to give, after chromatography (CH₂Cl₂to 5% MeOH/CH₂Cl₂),3-{3-[7-chlorobenzo-thiophene-2-carboxamido]propyl}-4-(2-methoxyethoxymethoxy)-benzonitrile.(0.020 g, 0.048 mmol); Ion Spray MS, [M+H]⁺=447. This material istreated with anhydrous HCl/EtOH followed by ammonolysis as described inEXAMPLE 307, part D. HPLC purification (10% MeCN/0.1% TFA in H₂O to 100%MeCN) gave the title compound (0.005 g, 0.012 mmol). ¹H NMR (DMSO, 300MHz) δ10.66 (s, 1H), 9.01 (s, 2H), 8.78 (m, 1H), 8.64 (bs, 2H), 8.22 (s,1H), 8.08 (s, 1H), 7.88 (d, 1H), 7.66 (d, 1H), 7.56 (dd, 1H), 7.47 (dd,21H), 6.95 (d, 1H), 3.32 (m, 2H), 2.65 (t, 2H), 1.86 (m, 2H). Ion sprayMS [M+1]⁺=388,390.

EXAMPLE 313

Compound 313

(E)-N-[3-(5-Carbamimidoyl-2-hydroxy-phenyl)-allyl]-4-(6-methoxy-pyridin-3-yl)-benzamidetrifluoroacetate

A.(E)-3-[3-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)propenyl]-4-(2-methoxy-ethoxymethoxy)benzonitrile

A solution of 2-bromo-4-cyanophenol (5 g, 25 mmol) and MEM chloride (3mL, 26 mmol) in THF (25 mL) is added to a suspension of NaH (60%, 1.1 g,28 mmol) in THF (25 mL) at 0° C. The resulting mixture is stirred atroom temperature for 2 h, concentrated, diluted with EtOAc, washed with1 N NaOH and water. The organic layer is dried over MgSO₄ andconcentrated to obtain a clear liquid (6.6 g, 23 mmol). The product (5.6g, 20 mmol) is treated with N-allylphthalimide (4 g, 21 mmol), Pd(OAc)₂(0.13 g, 0.58 mmol), P(o-tol)₃ (0.37 g, 1.2 mmol), and Et₃N (5.6 mL, 40mmol). The reaction mixture is heated at 100° C. in sealed tubeovernight, cooled, diluted with EtOAc and washed with water (3×100 mL).The organic layer is dried (MgSO₄) and concentrated. The residue ischromatographed (20% to 50% EtOAc/hexanes) to give the title compound asa white solid (3.5 g, 8.9 mmol). ¹H NMR (CDCl₃, 300 MHz) δ7.86 (m, 2H),7.72 (m, 2H), 7.65 (d, 1H), 7.44 (d, 1H), 7.18 (d, 1H), 6.90 (d, 1H),6.30 (m, 1H), 5.33 (s, 2H), 4.46 (d, 2H), 3.80 (d, 2H), 3.52 (d, 2H),3.40 (s, 3H).

B. (E)-3-(3-Aminopropenyl)-4-(2-methoxy-ethoxymethoxy)benzonitrile

(E)-3-[3-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)propenyl]-4-(2-methoxy-ethoxymethoxy)benzonitrile(3.1 g, 8.0 mmol) and NH₂NH₂ hydrate (0.96 mL, 20 mmol) in ethanol (100mL) is refluxed for 1.5 hours. The mixture is concentrated, treated withaqueous NaOH, and extracted with CH₂Cl₂ (3×). The CH₂Cl₂ layer is driedand concentrated to obtain the product as a clear oil (1.9 g, 7.2 mmol).¹H NMR (CDCl₃, 300 MHz) δ7.70 (d, 1H), 7.47 (dd, 1H), 7.22 (d, 1H), 6.75(d, 1H), 6.34 (m, 1H), 5.35 (s, 2H), 3.80 (t, 2H), 3.50 (m, 4H), 3.27(s, 3H).

C.(E)-N-[3-(5-Carbamimidoyl-2-hydroxy-phenyl)-allyl]-4-(6-methoxy-pyridin-3-yl)-benzamidetrifluoroacetate

A solution of(E)-3-(3-aminopropenyl)-4-(2-methoxy-ethoxymethoxy)benzonitrile (0.12 g,0.46 mmol) in DMF is treated with 6methoxy-pyridin-3-yl)-benzoic acid,TBTU and Et₃N as described in EXAMPLE 309, part B. Standard workup andchromatography gives the desired3-{3-[4-(6-oxo-1,6-dihydro-pyridin-3-yl)benzamido]propyl}-4-(2-methoxyethoxy-methoxy)-benzonitrile(0.22 g, 0.46 mmol). A portion of the benzonitrile (0.09 g, 0.19 mmol)is converted to the benzamidine by treatment with anhydrous HCl/EtOHfollowed by ammonolysis as described in EXAMPLE 307, part D. The productis purified by HPLC eluting with a gradient of 10% MeCN/H20 (0.1% TFA)to 100% MeCN to give title compound as a white solid (0.05 g, 0.12mmol). ¹H NMR (CD₃OD, 300 MHz) δ8.43 (d, 1H), 7.95 (m, 4H), 7.70 (d,2H), 7.55 (dd, 1H), 6.90 (m, 3H), 6.53 (m, 1H), 4.18 (d, 2H), 3.95 (s,3H). Ion spray MS [M+1]⁺=403.

EXAMPLE 314

Compound 314

(E)-N-[3-(5-Carbamimidoyl-2-hydroxy-phenyl)-allyl]-4-(6-oxo-1,6-dihydro-pyridin-3-yl)-benzamidetrifluoroacetate

(E)3-{3-[4-(6-methoxypyridin-3-yl)benzamido]propenyl}-4-(2-methoxyethoxymethoxy)-benzonitrile(0.12 g, 0.25 mmol), prepared as described in EXAMPLE 313, Part C, istreated with pyridinium hydrochloride as described in EXAMPLE 310, PartA to obtain a white solid (0.087 g, 0.24 mmol). This material is treatedwith anhydrous HCl/EtOH followed by ammonolysis as described in EXAMPLE307, part D. The crude product is purified by HPLC eluting with agradient of 10% MeCN/H₂O (0.1% TFA) to 100% MeCN, followed byrecrystallization (CH3CN/MeOH) to give title compound as a white solid(0.03 g, 0.077 mmol). ¹H NMR (DMSO, 300 MHz) δ11.92 (bs, 1H), 10.85 (s,1H), 9.03 (s, 2H), 8.82 (t, 1H), 8.65 (s, 2H), 7.85 (m, 5H), 7,65 (d,2H) 7.55 (d, 1H), 6.94 (d, 1H), 6,72 (d, 1H), 6.42 (m, 2H), 4.08 (t,2H). Ion spray MS [M+1]⁺=389.

EXAMPLE 315

Compound 315

(E)-Biphenyl-4-carboxylic acid[3-(5-carbamimidoyl-2-hydroxy-phenyl)-allyl]-amide trifluoroacetate

A solution of(E)-3-(3-aminopropenyl)-4-(2-methoxy-ethoxymethoxy)benzonitrile (0.04 g,0.2 mmol) in DMF (0.5 mL) is treated with Biphenyl-4-carboxylic acid(0.042 g, 0.21 mmol), TBTU (0.07 g, 0.22 mmol) and Et₃N (60 mL, 0.44mmol) for 4 hours at 35° C., then overnight at room temperature. Thereaction mixture is diluted with ethyl acetate (8 mL), washed with water(3×2 mL) and concentrated to a residue under a stream of nitrogen. Theresidue is treated with absolute ethanol (5 mL) cooled and saturatedwith HCl gas; the reaction container is sealed and the solution isstirred overnight at room tempera-ture. The solvent and excess HCl areremoved by a stream of nitrogen; the residue is dissolved in MeOH (5mL), cooled and saturated with NH₃ gas. The reaction container is sealedand the solution is stirred overnight at room temperature. The solventand excess NH₃ are removed by a stream of nitrogen. The residue issubjected to HPLC purification eluting with a gradient of 10% MeCN/H₂O(0.1% TFA) to 100% MeCN. Lyophylization of the appropriate fractiongives the title compound as a white solid (0.012 g, 0.032 mmol). ¹H NMR(CD₃OD, 300 MHz) δ8.84 (t, 1H), 7.92 (m, 3H), 7.70 (d, 2H), 7.65 (d,2H), 7.54 (dd, 1H), 7.42 (m, 3H), 6.92 (m, 2H), 6.50 (m, 1H), 4.20 (t,2H). Ion spray MS [M+1]⁺=372.

In a like manner, by the method described in EXAMPLE 315, the compoundsof EXAMPLES 316-324 are prepared:

EXAMPLE 316

Compound 316

(E)-N-[3-(5-Carbamimidoyl-2-hydroxy-phenyl)-allyl]-4-pyridin-3-yl-benzamideditrifluoroacetate

The title compound is prepared from(E)-3-(3-aminopropenyl)-4-(2-methoxy-ethoxymethoxy)benzonitrile and4pyridin-3-yl-benzoic acid. ¹H NMR (DMSO, 300 MHz) δ10.87 (s, 1H), 9.05(s, 2H), 9.00 (s, 1H), 8.90 (t, 1H), 8.73 (s, 2H), 8.61 (d, 1H), 8.25(d, 1H), 8.00 (d, 2H), 7.85 (m, 3H), 7,57 (m, 2H), 6.95 (d, 1H), 6.70(d, 1H), 6.45 (m, 1H), 4.08 (t, 2H). Ion spray MS [M+1]+=373,[M+2]²+=187.

EXAMPLE 317

Compound 317

(E)-N-[3-(5-Carbamimidoyl-2-hydroxy-phenyl)-allyl]-4-pyridin-4-yl-benzamideditrifluoroacetate

The title compound is prepared from(E)-3-(3-aminopropenyl)-4-(2-methoxy-ethoxymethoxy)benzonitrile and4-pyridin-4-yl-benzoic acid. ¹H NMR (CD₃OD, 300 MHz) δ8.97 (t, 1H), 8.80(d, 2H), 8.22 (d, 2H), 8.00 (m, 5H), 7.55 (dd, 1H), 6.90 (m, 2H), 6.55(m, 1H), 4.22 (t, 2H). Ion spray MS [M+1]⁺=373, [M+2]²⁺=187.

EXAMPLE 318

Compound 318

(E)-Biphenyl-3,4′-dicarboxylic acid 3-amide4′-{[3-(5-carbamimidoyl-2-hydroxy-phenyl)-allyl]-amide}trifluoroacetate

The title compound is prepared from(E)-3-(3-aminopropenyl)-4-(2-methoxy-ethoxymethoxy) benzonitrile andbiphenyl-3,4′-dicarboxylic acid 3-amide. ¹H NMR (CD₃OD, 300 MHz) δ8.87(t, 1H), 8.18 (s, 1H), 7.96 (d, 2H), 7.85 (m, 5H), 7.55 (m, 2H), 6.95(m, 2H), 6.53 (m, 1H), 4.21 (t, 2H). Ion spray MS [M+1]⁺=415.

EXAMPLE 319

Compound319

(E)-4-tert-Butyl-N-[3-(5-carbamimidoyl-2-hydroxy-phenyl)-allyl]-benzamidetrifluoroacetate

The title compound is prepared from(E)-3-(3-aminopropenyl)-4-(2-methoxy-ethoxymethoxy)benzonitrile and4-tert-butylbenzoic acid. ¹H NMR (CD₃OD, 300 MHz) δ8.72 (t, 1H), 7.90(d, 1H), 7.78 (d, 2H), 7.50 (m, 3H), 6.90 (m, 2H), 6.50 (m, 1H), 4.17(t, 2H), 1.34 (s 9H). Ion spray MS [M+1]^(+=352.)

EXAMPLE 320

Compound 320

(E)-N-[3-(5-Carbamimidoyl-2-hydroxy-phenyl)-allyl]-4-(3H-imidazol-4-yl)-benzamideditrifluoroacetate

The title compound is prepared from(E)-3-(3-aminopropenyl)-4-(2-methoxy-ethoxymethoxy) benzonitrile and4-(3H-imidazol-4-yl)benzoic acid. ¹H NMR (CD₃OD, 300 MHz) δ8.90 (m, 2H),8.00 (m, 3H), 7.90 (d, 1H), 7.85 (d, 2H), 7.57 (dd, 1H), 6.93 (m, 2H),6.53 (m, 1H), 4.20 (t, 2H). Ion spray MS [M+1]⁺=362, [M+2]²⁺=181.4.

EXAMPLE 321

Compound 321

(E)-Biphenyl-4,4′-dicarboxylic acid 4′-amide4-{[3-(5-carbamimidoyl-2-hydroxy-phenyl)-allyl]-amide}trifluoroacetate

The title compound is prepared from(E)-3-(3-aminopropenyl)-4-(2-methoxy-ethoxymethoxy) benzonitrile andbiphenyl-4,4′-dicarboxylic acid 4′-amide. ¹H NMR (CD₃OD, 300 MHz) δ8.87(t, 1H), 7.96 (m, 5H), 7.79 (m, 4H), 7.55 (d, 1H), 6.90 (m, 2H), 6.50(m, 1H), 4.22 (t, 2H). Ion spray MS [M+1]⁺=415.

EXAMPLE 322

Compound 322

(E)-N-[3-(5-Carbamimidoyl-2-hydroxy-phenyl)-allyl]-4-(1H-imidazol-2-yl)-benzamideditrifluoroacetate

The title compound is prepared from(E)-3-(3-aminopropenyl)-4-(2-methoxy-ethoxymethoxy) benzonitrile and4-(1H-imidazol-2-yl)-benzoic acid. ¹H NMR (CD₃OD,300 MHz) δ9.02 (t, 1H),8.08 (d, 2H), 8.00 (d, 2H), 7.90 (d, 1H), 7.67 (s, 2H), 7.53 (dd, 1H),6.90 (m, 2H), 6.53 (m, 1H), 4.9 (t, 2H). Ion spray MS [M+1]⁺=362,[M+2]²⁺=181.6.

EXAMPLE 323

Compound 323

(E)-3-Oxo-2,3-dihydro-thieno[3,2-c]pyridazine-6-carboxylic acid[3-(5-carbamimidoyl-2-hydroxy-phenyl)-allyl]-amide trifluoroacetate

The title compound is prepared from(E)-3-(3-aminopropenyl)-4-(2-methoxy-ethoxymethoxy) benzonitrile and3-oxo-2,3-dihydro-thieno[3,2-c]pyridazine-6-carboxylic acid. ¹H NMR(CD₃OD, 300 MHz) δ7.90 (d, 1H), 7.74 (s, 1H), 7.55 (dd, 1H), 7.40 (s,1H), 6.90 (m, 2H), 6.49 (m, 1H), 4.13 (d, 2H). Ion spray MS [M+1]⁺=370.

EXAMPLE 324

Compound 324

(E)-5-Pyridin-2-yl-thiophene-2-carboxylic acid[3-(5-carbamimidoyl-2-hydroxy-phenyl)-allyl]-amide ditrifluoroacetate

The title compound is prepared from(E)-3-(3-aminopropenyl)-4-(2-methoxy-ethoxymethoxy) benzonitrile and5-pyridin-2-yl-thiophene-2-carboxylic acid. ¹H NMR (CD₃OD, 300 MHz)δ8.97 (bs, 1H), 8.50 (m, 2H), 7.87 (m, 3H), 7.70 (m, 2H), 7.55 (dd, 1H),7.30 (m, 1H), 6.89 (m, 2H), 6.47 (m, 1H), 4.15 (d, 2H). Ion spray MS[M+1]⁺=379, [M+2]²⁺=190.

EXAMPLE 325

Compound 325

(E)-N-[3-(5-Carbamimidoyl-2-hydroxy-phenyl)-allyl]-4-(1-oxy-pyridin-4-yl)-benzamideditrifluoroacetate

A. 4-(1-Oxy-pyridin-4-yl)-benzoic acid

4-Pyridin-4-yl-benzoic acid methyl ester (0.32 g, 1.6 mmol) in CH₂Cl₂(30 ml) is treated with MCPBA (50-60%, 0.88 g) at 0° C., and stirred atroom temperature for 3 h. The reaction is quenched with 1 N NaOH; theCH₂Cl₂ layer is washed with H₂O, dried and concentrated to a give solid4-(1-oxy-pyridin-4-yl)-benzoic acid methyl ester (0.23 g, 1.0 mmol).This material is treated with 1 N NaOH (1 ml) in MeOH/THF/H₂O (1 ml/1ml/3 ml) at room temperature for 3 h, then neutralized with 1 N HCl topH˜6. The off-white solid is collected and washed with acetone to give4-(1-oxypyridin-4-yl)-benzoic acid (0.12 g, 0.56 mmol). ¹H NMR (DMSO-d₆,300 MHz) δ8.27 (d, 2H), 8.0 (d, 2H), 7.88 (d, 2H), 7.83 (d, 2H).

B.(E)-N-[3-(5-Carbamimidoyl-2-hydroxy-phenyl)-allyl]-4-(1-oxy-pyridin-4-yl)-benzamideditrifluoroacetate

The title compound is prepared from(E)-3-(3-aminopropenyl)-4-(2-methoxy-ethoxymethoxy) benzonitrile and4-(1-oxypyridin-4-yl)-benzoic acid essentially as described in EXAMPLE307, Part D. ¹H NMR (DMSO-d₆, 300 MHz) δ8.98 (bs, 1H), 8.50 (bs, 1H),8.42 (d, 2H), 8.02 (d, 2H), 7.95-7.88 (m, 5H), 7.56 (dd, 1H), 6.94 (d,1H), 6.88 (d, 1H), 6.50 (m, 1H), 4.18 (d, 2H). APCI MS, [M+H]⁺=389.

EXAMPLE 326

Compound 326

Biphenyl-4-carboxylic acid[3-(5-carbamimidoyl-2-hydroxy-phenyl)-propyl]-amide trifluoroacetate

(E)-biphenyl-4-carboxylic acid[3-(5-carbamimidoyl-2-hydroxy-phenyl)-allyl]-amide trifluoroacetate(0.006, 0.0012 mmol), prepared as described in EXAMPLE 315, is dissolvedin methanol (5 mL), treated with a catalytic amount of 10% palladium oncarbon and stirred under an atmosphere of hydrogen gas overnight. Thesolid is removed by filtration; the filtrate is concentrated by a streamof nitrogen. The residue is subjected to HPLC purification eluting witha gradient of 10% MeCN/H₂O (0.1% TFA) to 100% MeCN. Lyophylization ofthe appropriate fraction yields the title compound as a white solid(0.006 g, 0.012 mmol). ¹H NMR (CD₃OD, 300 MHz) δ7.90 (d, 2H), 7.70-7.60(m, 5H), 7.54-7.35 (m, 4H), 6.90 (d, 1H), 3.43 (t, 2H), 2.75 (t, 2H),1.97 (m, 2H). APCI MS [M+1]⁺=374.

In a like manner, by the method described in EXAMPLE 326, the compoundsof EXAMPLES 327-332 are prepared:

EXAMPLE 327

Compound 327

N-[3-(5-Carbamimidoyl-2-hydroxy-phenyl)-propyl]-4-(6-methoxy-pyridin-3-yl)-benzamidetrifluoroacetate

The title compound is prepared from reduction of(E)-N-[3-(5-carbamimidoyl-2-hydroxy-phenyl)-allyl]-4-(6-methoxy-pyridin-3-yl)-benzamidetrifluoroacetate. ¹H NMR (CD₃OD, 300 MHz) δ8.93 (bs, 1H), 8.50 (m, 2H),8.00 (d, 1H), 7.90 (d, 2H), 7.68 (d, 2H), 7.64 (d, 1H), 7.55 (dd, 1H),6.92 (d, 2H), 3.97 (s, 3H), 3.44 (t, 2H), 2.76 (t, 2H), 1.97 (m, 2H).APCI MS [M+1]⁺405.

EXAMPLE 328

Compound 328

Biphenyl-3,4′-dicarboxylic acid 3-amide4′-{[3-(5-carbamimidoyl-2-hydroxy-phenyl)-propyl]-amide}trifluoroacetate

The title compound is prepared from reduction of(E)-biphenyl-3,4′-dicarboxylic acid 3-amide4′-{[3-(5-carbamimidoyl-2-hydroxy-phenyl)-allyl]-amide}trifluoroacetate. ¹H NMR (CD₃OD, 300 MHz) δ8.17 (s, 1H), 7.94-7.76 (m,6H), 7.65-7.52 (m, 3H), 6.92 (d, 1H), 3.44 (t, 2H), 2.75 (t, 2H), 1.97(m, 2H). APCI MS [M+1]⁺=417.

EXAMPLE 329

Compound 329

4-tert-Butyl-N-[3-(5-carbamimidoyl-2-hydroxy-phenyl)-propyl]-benzamidetrifluoroacetate

The title compound is prepared from reduction of(E)-4-tert-butyl-N-[3-(5-carbamimidoyl-2-hydroxy-phenyl)-allyl]-benzamidetrifluoroacetate. ¹H NMR (CD₃OD, 300 MHz) δ7.74 (d, 2H), 7.60 (d, 1H),7.50 (m, 3H), 6.89 (d, 1H), 3.39 (t, 2H), 2.74 (t, 2H), 1.94 (m, 2H),1.33 (s, 9H). APCI MS [M+1]⁺=354.

EXAMPLE 330

Compound 330

[3-(5-Carbamimidoyl-2-hydroxy-phenyl)-propyl]-4-(3H-imidazol-4-yl)-benzamideditrifluoroacetate

The title compound is prepared from reduction of(E)-[3-(5-carbamimidoyl-2-hydroxy-phenyl)-allyl]-4-(3H-imidazol-4-yl)-benzamideditrifluoroacetate. ¹H NMR (CD₃OD, 300 MHz) δ8.97 (s, 1H), 8,65 (t, 1H),7.99 (m, 3H), 7.84 (d, 2H), 7.64 (d, 1H), 7.57 (dd, 1H), 6.93 (d, 1H),3.44 (m, 2H), 2.76 (t, 2H), 1.98 (m, 2H). APCI MS [M+1]⁺=364.

EXAMPLE 331

Compound 331

N-[3-(5-Carbamimidoyl-2-hydroxy-phenyl)-propyl]-4(1H-imidazol-2-yl)-benzamideditrifluoroacetate

The title compound is prepared from reduction of(E)-N-[3-(5-carbamimidoyl-2-hydroxy-phenyl)-allyl]-4-(1H-imidazol-2-yl)-benzamideditrifluoroacetate. ¹H NMR (CD₃OD, 300 MHz) δ8.77 (t, 1H), 8.06 (m, 4H),7.69 (s, 2H), 7.65 (d, 1H), 7.57 (dd, 1H), 6.93 (d, 1H), 3.44 (m, 2H),2.76 (t, 2H), 1.97 (m, 2H). APCI MS [M+1]⁺=364.

EXAMPLE 332

Compound 332

5-Pyridin-2-yl-thiophene-2-carboxylic acid[3-(5-carbamimidoyl-2-hydroxy-phenyl)-allyl]-amide ditrifluoroacetate

The title compound is prepared from reduction of(E)-5-pyridin-2-yl-thiophene-2-carboxylic acid[3-(5-carbamimidoyl-2-hydroxy-phenyl)-allyl]-amide ditrifluoroacetate.¹H NMR (CD₃OD, 300 MHz) δ8.92 (bs, 1H), 8.50 (m, 2H), 7.90 (m, 2H), 7.68(m, 2H), 7.60 (d, 1H), 7.54 (dd, 1H), 7.34 (m, 1H), 6.89 (d, 1H), 3.38(t, 2H), 2.76 (t, 2H), 1.97 (m, 2H). APCI MS [M+1]³⁰ =381.

EXAMPLE 333

Compound 333

N-[3-(5-Carbamimidoyl-2-hydroxy-phenyl)-propyl]-4-piperidin-4yl-benzamideditrifluoroacetate

(E)-N-[3-(5-Carbamimidoyl-2-hydroxy-phenyl)-allyl]-4-pyridin-4-yl-benzamideditrifluoroacetate is treated as described in EXAMPLE 326 then subjectedto 50 psi of hydrogen gas for 5 hours in the presence of 10% Pd/C. Thetitle compound (0.005 g, 0.008 mmol) is obtained by filtration andconcentration of the filtrate to dryness. ¹H NMR (CD₃OD, 300 MHz) δ8.50(bs, 1H), 7.80 (d, 2H), 7.59 (d, 1H), 7.55 (dd, 1H), 7.37 (d, 2H), 6.93(d, 1H), 3.5-2.9 (m, 7H), 2.75 (t, 2H), 2.1-1.9 (m, 6H). Ion spray MS[M+1]⁺=381, [M+2]²⁺=191.

EXAMPLE 334

2-(3-Carbamimidoyl-benzyl)-3-[4-(1-oxy-pyridin-4-yl)-benzoylamino]-butyricacid methyl ester hydrochloride (0.60 g, 1.1 mmol) is dissolved in 15%MeCN/H₂O and treated with 1.0 N NaOH (6 ml). The mixture is stirred for2 h at room temperature, and then acidified with TFA. The crude productis purified by HPLC eluting in a gradient of 10% MeCN/H₂O (0.1% TFA) to100% MeCN. The product fractions are lyophilized to provide the titlecompound as a white solid (0.43 g, 0.92 mmol). ¹H NMR (DMSO-D₆, 300 MHz)δ9.25 (s, 2H), 9.0 (s, 2H), 8.38 (d, 1H), 8.28 (d, 2H), 7.92-7.46 (m,4H), 4.40 (m, 1H), 2.94 (m, 3H), 1.23 (d, 3H). Fab MS, [M+H]⁺=433.

EXAMPLE 335

2(R)-(3-Carbamimidoylbenzyl)-3-(R)-[(3′-nitrobiphenyl-4-carbonyl)amino]-butyricacid methyl ester trifluoroacetate is prepared by proceduressubstantially similar to those described above, starting fromappropriate materials. ¹H NMR (DMSO-d₆, 300 MHz) δ8.40-8.52 (m, 2H),8.15-8.30 (m, 2H), 7.85-8.0 (m, 4H), 7.75-7.82 (m, 1H), 7.52 (s, 1H),4.35-4.51 (m, 1H), 3.47 (s, 3H), 3.04-3.15 (m, 1H), 2.90-3.03 (m, 2H),1.23 (d, 3H). Ion Spray MS, [M+H]⁺=490.

EXAMPLE 336

2(R)-3-Carbamimidoyl-benzyl)-3(R)-(4-pyridin-2-yl-benzoylamino)-butyricacid methyl ester ditrifluoroacetate is prepared by proceduressubstantially similar to those described above, starting fromappropriate materials. ¹H NMR (CD₃OD, 300 MHz) δ8.68 (d, 1H), 7.92-8.11(m, 6H), 7.47-7.68 (m, 5H), 4.40-4.55 (m, 1H), 3.62 (s, 3H), 3.02-3.18(m, 3H), 1.32 (d, 3H). Ion spray MS [M+1]⁺=431.

EXAMPLE 337

2(R)-(3-Carbamimidoyl-benzyl)-3(R)-[4-(1oxy-pyridin-2-yl)-benzoylamino]-butyricacid methyl ester-trifluoroacecate is prepared by proceduressubstantially similar to those described above, starting fromappropriate materials. ¹H NMR (CD₃OD, 300 Mhz) δ8.46 (d, 1H), 7.92 (m,4H), 7.67-7.77 (m, 2H), 7.45-7.66 (m, 5H), 4.40-4.55 (m, 1H), 3.60 (s,3H), 3.02-3.18 (m, 3H), 3.02-3.18 (m, 3H), 1.34 (d, 3H). Ion spray MS[M+1]⁺=447.

EXAMPLE 338

2-{4-[3-(3-Carbamimidoyl-phenyl)-2(R)-methoxycarbonyl-1(R)-methyl-propylcarbamoyl]-phenyl}-1-methyl-pyridinium-ditrifluoroacetateis prepared by procedures substantially similar to those describedabove, starting from appropriate materials. ¹H NMR (CD₃OD, 300 Mhz)δ9.04 (d, 1H), 8.66 (m, 1H), 8.02-8.18 (m, 4H), 7.79 (d, 2H), 7.45-7.70(m, 4H), 4.38-4.50 (m, 1H), 4.22 (s, 3H), 3.60 (s, 3H), 3.03-3.18 (m,3H), 1.38 (s, 3H). Fab MS [M+]⁺=445.

EXAMPLE 339

2-(R)-(3-Carbamimidoylbenzyl)-3-(R)-[(3′,4′-dimethoxybiphenyl-4-carbonyl)amino]-butyricacid methyl ester trifluoroacetate is prepared by proceduressubstantially similar to those used to prepare compound 216, startingfrom the appropriate materials. ¹H NMR (DMSO-d₆, 300 MHz) δ8.32 (d, 1H),7.82-7.9 (m, 2H), 7.71-7.78 (m, 2H), 7.61 (s, 1H), 7.52 (m, 2H)7.22-7.30 (m, 2H), 7.06 (d, 1H) 4.08-4.35 (m, 1H), 3.83 (s, 3H), 3.78(s, 3H), 3.50 (s, 3H), 3.03-3.13 (m, 1H), 2.92-3.02 (m, 2H), 1.25 (d,3H). Ion Spray MS, [M+H]⁺=490.

EXAMPLE 340

2-(R)-(3-Carbamimidoyl-benzyl)-3(R)-{[4-(1-oxy-pyridin-2-yl)-thiophene-2-carbonyl]-amino}-butyricacid methyl ester trifluoroacetate is prepared by proceduressubstantially similar to those described above, starting fromappropriate materials. ¹H NMR (CD₃OD, 300 Mhz) δ8.73 (s, 1H), 8.42 (d,1H), 8.37 (m, 2H), 7.92-7.98 (m, 1H), 7.42-7.68 (m, 5H), 4.35-4.48 (m,1H), 3.60 (s, 3H), 3.01-3.20 (m, 3H), 1.32 (d, 3H), Ion spray MS[M+1]⁺=453.

EXAMPLE 341

2-{5-[3-(3-Carbamimidoyl-phenyl-2(R)-methoxycarbonyl-1(R)-methyl-propylcarbamoyl]-thiophen-3-yl}-1-methyl-pyridiniumditrifluoroacetate is prepared by procedures substantially similar tothose described above, starting from appropriate materials. ¹H NMR(CD₃OD, 300 Mhz) δ8.99 (d, 1H), 8.60 (m, 1H), 8.28 (s, 1H), 8.02-8.17(m, 3H), 7.45-7.68 (m, 4H), 4.38-4.50 (m, 1H), 4.32 (s, 3H), 3.55 (s,3H), 3.02-3.15 (m, 3H), 1.34 (d, 3H). Fab MS [M+]⁺=451.

EXAMPLE 342

2-(R)-(3-Carbamimidoylbenzyl)-3-(R)-{oxypyridin-3yl)-thiophene-2-carbonyl}-amino}butyricacid methyl ester trifluoroacetate is prepared by proceduressubstantially similar to those described above, starting fromappropriate materials. ¹H NMR (CD₃OD, 300 MHz) δ8.67 (s, 1H), 8.36 (d,1H), 8.30 (dd, 1H), 8.21 (s, 1H), 8.12 (s, 1H), 7.93 (dd, 1H), 7.45-7.68(m, 4H), 4.37-51 (m, 1H), 3.61 (s, 3H), 3.02-3.18 (m, 3H), 1.32 (d, 3H).Ion Spray MS, [M+H]⁺=453.

EXAMPLE 343

3-{5-[3-(3-Carbamimidoylphenyl)-2-(R)-methoxycarbonyl-1-(R)-methyl-propylcarbamoyl]-thiophen-3-yl}-1-methylpyridiniumditrifluoroacetate is prepared by procedures substantially similar tothose described above, starting from appropriate materials. ¹H NMR(CD₃OD, 300 MHz) δ9.34 (s, 1H), 8.80-8.88 (m, 2H), 8.36 (s, 1H), 8.25(s, 1H), 8.09-8.17 (m, 1H), 7.48-7.68 (m, 4H), 4.46 (s, 3H), 4.37-4.45(m, 1H), 3.58 (s, 3H), 3.02-3.18 (m, 3H), 1.33 (d, 3H). Ion Spray MS,M⁺=451.

EXAMPLE 344

Compound 344

2-(R)-(3-Carbamimidoyl-benzyl)-3(R)-[4-(6-oxo-1,6-dihydro-pyridin-3-yl)-benzoylamino]-butyricacid methyl ester trifluoroacetate

A. 4-(6-methoxy-pyridin-3-yl)-benzoic acid ethyl ester

A 1.6 M solution of nBuLi in hexane (9.53 mL, 15.24 mmol) is addeddropwise to a stirred solution of 5-Bromo-2-methoxy-pyridine (2.72 g,14.52 mmol) in THF (50 mL) at −78° C. The resulting mixture is stirredfor 15 minutes at −78° C. To this is added a 0.5 M solution of ZnCl₂ inTHF (29.04 mL, 14.52 mmol) and the resulting mixture allowed to warm toroom temperature. In a separate flasktetrakis(triphenylphosphine)palladium(O) (0.58 g, 0.50 mmol) is stirredin THF (10 mL). To this is added 4-ethyl-iodobenzoate (3.61 g, 13.07mmol). The contents of the two flasks are combined and stirred for 1hour at room temperature. A 5% solution of ammonia in water (150 mL) isadded with stirring. The mixture is extracted with EtOAc (3×). Theorganics are combined and dried over MgSO₄, filtered and concentrated.The crude product is purified by flash chromatography (2.5% EtOAc/hexaneto 5% EtOAc/hexane) to give the product as a white solid (2.43g, 9.44mmol). ¹H NMR (CDCl₃, 300 MHz) d 8.41 (d, 1H), 8.08 (d, 2H), 7.82 (dd,1H), 7.60 (d, 2H), 6.82 (d, 1H), 4.38 (q, 2H), 3.98 (s, 3H), 1.40 (t,3H).

B. 4-(6-methoxy-pyridin-3-yl)-benzoic acid

A 1N sodium hydroxide solution (20 mL) is added to a mixture of4-(6-methoxy-pyridin-3-yl)-benzoic acid ethyl ester (2.43 g, 9.44 mmol)in MeOH (20 mL) and THF (20 mL) and stirred at 35° C. for 1 hour. Thereaction is cooled and 1N HCl added until the pH is˜4. The precipitateis isolated by filtration and dried in a vacuum desiccator to give a theproduct as a white solid (2.03 g, 8.86 mmol). ¹H NMR (DMSO-d₆, 300 MHz)δ8.57 (d, 1H), 8.08 (dd, 1H), 7.99 (d, 2H), 7.82 (d, 2H), 6.95 (d, 1H),3.89 (s, 3H).

C.2-(R)-(3-Cyano-benzyl)-3(R)-[4-(6-methoxy-pyridin-3-yl)-benzoylamino]-butyricacid methyl ester

To a stirred solution of 4-(6-methoxy-pyridin-3-yl)-benzoic acid (0.67g, 2.54 mmol) in DMF (5 mL) is added DIPEA (0.44 mL, 2.54 mmol), TBTU(0.91 g, 2.54 mmol) and 2(R)-(3-Cyano-benzyl)-3(R)-amino-butyric acidmethyl ester (0.59 g, 2.54 mmol). The solution is stirred overnight atroom temperature. The reaction is diluted with EtOAc and washed withsaturated sodium bicarbonate (3×), brine, dried over MgSO₄, filtered andconcentrated. The crude product is purified by flash chromatography (50%EtOAc/hexane to 60% EtOAc/hexane) to give the product as a white solid(0.83 g, 1.87 mmol). ¹H NMR (CDCl₃, 300 MHz) δ8.43 (d, 1H), 7.92 (d,2H), 7.83 (dd, 1H), 7.63 (d, 1H), 7.30-7.55 (m, 4H), 6.87 (d, 1H),4.42-4.53 (m, 1H), 3.98 (s, 3H), 3.66 (s, 3H), 2.85-3.08 (m, 3H), 1.28(d, 3H).

D.2-(R)-(3-Cyano-benzyl)-3(R)-[4-(6-oxo-1,6-dihydro-pyridin-3-yl)-benzoylamino]-butyricacid methyl ester.

A mixture of2-(R)-(3-Cyano-benzyl)-3(R)-[4-(6-methoxy-pyridin-3-yl)-benzoylamino]-butyricacid methyl ester (0.80 g, 1.805 mmol) and pyridine hydrochloride (3.37g, 21.6 mmol) is heated for 10 minutes at 160° C. The reaction is cooledto room temperature and water added (40 mL). The resulting mixture ispartitioned between methylene chloride and saturated sodium bicarbonate.The organic layer is washed with saturated sodium bicarbonate (2×),brine, dried over MgSO₄, filtered and concentrated to give the crudeproduct as a tan foam (0.82 g). ¹H NMR (CDCl₃, 300 Mhz) δ7.78-7.95 (m,3H), 7.65-7.73 (m, 1H), 7.28-7.57 (m, 6H), 6.45 (d, 1H), 4.41-4.54 (m,1H), 3.66 (s, 3H), 2.82-3.07 (m, 3H), 1.28 (d, 3H).

E.2-(R)-(3-Carbamimidoyl-benzyl)-3(R)-[4-(6oxo-1,6-dihydro-pyridin-3-yl)-benzoylamino]-butyricacid methyl ester-trifluoroacetate

This compound is prepared by procedures substantially similar to thosedescribed above, starting with2-(R)-(3-Cyano-benzyl)-3(R)-[4-(6-oxo-1,6-dihydro-pyridin-3-yl)-benzoylamino]-butyricacid methyl ester. ¹H NMR (DMSO-d₆, 300 MHz) δ8.32 (d, 1H), 7.88 (d,1H), 7.81-7.83 (m, 2H), 7.65-7.69 (m, 2H), 7.55-7.63 (m, 2H), 7.45-7.52(m, 2H), 6.45 (d, 1H), 4.32-4.48 (m, 1H), 3.48 (s, 3H), 3.01-3.11 (m,1H), 2.88-2.98 (m, 2H), 1.22 (d, 3H). Ion spray MS [M+1]⁺=447.

EXAMPLE 345

A. 3-(4-(Pyridin-3-yl)-benzoylamino)-propionic acid t-butyl ester

To a suspension of 4-(pyridin-3-yl)-benzoic acid (1.32 g, 6.6 mmol) inCH₂Cl₂ (26 mL) is added DMF (8 ml, 0.5 mmol) followed by oxalyl chloride(6.6 mL, 2M in CH₂Cl₂). The resulting suspension is stirred for 3 hrthen concentrated under vacuum. To this residue is addedt-butyl-(3-amino)-propionionate hydrochloride (1.089 g, 6 mmol). Thismixture is diluted with CH₂Cl₂ (26 mL) cooled to 0° C. then Et₃N added(3.3 mL, 24 mmol). The resulting mixture is stirred for 3 hr. thendiluted with ethyl acetate:CH₂Cl₂ (approx. 2:1), washed with water (3×),then brine, dried over MgSO₄ and concentrated. The residue is purifiedby flash chromatography (60% ethyl acetate in CH₂Cl₂ to give 1.22 g ofthe title compound as a white solid. ¹H NMR (CDCl₃) δ1.49 (s, 9H), 2.59(t, J=7 Hz, 2H), 3.73 (q, J=7 Hz, 2H), 6.98 (bt, J=7 Hz, 1H), 7.40 (m,1H), 7.67 (d, J=8 Hz, 2H), 7.89 (m, 3H), 8.63 (bd, 1H), 8.88 (bs, 1H).MS m/z 327 (M+H).

B.2-(5-Iodo-2-(2-methoxy-etboxymethoxy)-benzyl)-3-(4-(pyridin-3-yl)benzoylamino)-propionicacid t-butyl ester

To a cooled (−15° C.) solution of diisopropylamine (1.6 mL, 11.5 mmol)in THF (20 mL), is added dropwise n-BuLi (4.6 mL, 2.5 M in hexanes). Theresulting solution is stirred for 10 min then cooled to−78° C. over 10min. To this solution is added a solution of3-(4-(pyridin-3-yl)-benzoylamino)-propionic acid t-butyl ester. (1.65 g,5 mmol) in THF/DMPU (6 mL, 1/1). On complete addition, the reactionmixture is warmed to −40° C. over 15 min. To this solution is added asolution of bromide (2.13 g, 5.3 mmol) in THF (10 mL). The reactionmixture is stirred for 20 min then HCl (5 ml, 1M) added. This mixture isdiluted with ethyl acetate, washed with water and brine, dried overMgSO₄ and concentrated. The residue is purified by flash chromatography(eluting with 80% ethyl acetate in hexanes) to give 3.03 g of the titlecompound as a foam. ¹H NMR (CDCl₃) δ1.40 (s, 9H), 2.81 (m, 1H), 2.95 (m,1H), 3.06 (m, 1H), 3.47 (s, 3H), 3.54 (m, 2H), 3.68 (m, 2H), 3.80 (m,2H), 5.29 (s, 2H), 6.91 (m, 2H), 7.40 (m, 1H), 7.47 (m, 2H), 7.66 (d,J=8 Hz, 2H), 7.89 (m, 2H), 8.64 (bd, 1H), 8.88 (bs, 1H). MS m/z 647(M+H).

C.2-(5-Iodo-2-hydroxy-benzyl)-3-(4-(pyridin-3-yl)-benzoylamino-propionicacid methyl ester

To a solution of2-(5-iodo-2-(2-methoxy-ethoxymethoxy)-benzyl)-3-(4-(pyridin-3-yl)-benzoylamino)-propionicacid t-butyl ester (3.03 g, 4.69 mmol) in CH₂Cl₂ (25 mL) is added TFA (5mL). The resulting solution is stirred for 19 hr then concentrated toapprox. half the original volume. To this solution is added toluene (20mL). This solution is concentrated under reduced pressure. The residueis dissolved in THF (20 mL) and cooled to −10° C. To this solution isadded NaOMe (2.3 mL, 25% wt in MeOH). After stirring 10 min. thereaction mixture is brought to pH 6 with hydrochloric acid (1 M). Thismixture is diluted with ethyl acetate, washed with water and brine,dried over MgSO₄ and concentrated. The residue is purified by flashchromatography (eluting with 80% ethyl acetate in hexanes) to give 2.13g of the title compound. ¹H NMR (CDCl₃) δ3.01 (m, 3H), 3.68 (m, 2H),3.70 (s, 3H), 6.67 (d, J=8 Hz, 1H), 7.39 (m, 3H), 7.48 (d, J=8 Hz, 2H),7.85 (m, 3H), 8.6 (dd, 1H), 8.70 (d, 1H), 9.40 (bs, 1H). MS m/z 517(M+H).

D.2-(5-cyano-2-hydroxy-benzyl)-3-(4-(pyridin-3-yl)-benzoylamino-propionicacid methyl ester

To a mixture of2-(5-iodo-2-hydroxy-benzyl)-3-(4-(pyridin-3-yl)-benzoylamino)-propionicacid methyl ester (2.1 g, 4.07 mmol) (Ph₃P)₄Pd (460 mg, 0.4 mmol) andZnCN₂ (1.42 g, 12.2 mmol) is added DMF (20 mL). The resulting mixture isdegassed and purged with argon then placed in an oil bath held at 73° C.The reaction mixture is stirred at this temperature for 90 min. thencooled diluted with ethyl acetate and washed with water. The aqueousfraction is extracted with ethyl acetate:CH₂Cl₂ (4:1, 3×). The combinedorganic extract is dried over MgSO₄ and concentrated. The residue ispurified by flash chromatography (eluting with 90% ethyl acetate inCH₂Cl₂) to give 1.53 g of the title compound. ¹H NMR (CDCl₃) 83.03 (m,1H), 3.16 (m, 1H), 3.68 (m, 3H), 3.70 (s, 3H), 6.93 (d, J=8 Hz, 1H),7.39 (m, 3H), 7.50 (d, J=8 Hz, 2H), 7.95 (m, 3H), 8.6 (dd, 1H), 8.71 (d,1H). MS m/z 416 (M+H).

E.2-(5-Carbamimidoyl-2-hydroxy-benzyl)-3-(4-(pyridin-3-yl)-benzoylamino-propionicacid methyl ester

2-(5-cyano-2-hydroxy-benzyl)-3-(4-(pyridin-3-yl)-benzoylamino-propionicacid methyl ester (623 mg, 1.5 mmol) is dissolved in a saturatedsolution of HCl in methanol (15 mL). This solution is stirred for 5 hr.then concentrated under reduced pressure. The residue is taken up in asaturated solution of NH₃ in MeOH (10 mL) and stirred for 18 hr thenconcentrated under reduced pressure. The residue is purified by flashchromatography (eluting with 1% Et₃N/10% EtOAc in CH₂Cl₂) to give 343 mgof the title compound as a solid. ¹H NMR (CD₃OD) δ2.88 (m, 1H), 3.08 (m,2H), 3.50 (m, 1H), 3.67 (s, 3H), 3.68 (m, 1H), 6.68 (d, J=8 Hz, 1H),7.50 (m, 3H), 7.78 (d, J=8 Hz, 2H), 8.0 (d, J=8 Hz, 2H), 8.14 (m, 1H),8.55 (d, 1H), 8.86 (bs, 1H). MS m/z 433 (M+H).

EXAMPLE 346

By the methods described above is prepared2(R)-(3-Carbamimidoyl-6-hydroxybenzyl)-3(R)-[4-(6-oxo-1,6-dihydro-pyridin-3-yl)-benzoylamino]-butyricacid methyl ester.

The molecules described herein inhibit blood coagulation by virtue oftheir ability to inhibit the penultimate enzyme in the coagulationcascade, factor Xa, rather than thrombin. Both free factor Xa and factorXa assembled in the prothrombinase complex (Factor Xa, Factor Va,calcium and phospholipid) are inhibited. Factor Xa inhibition isobtained by direct complex formation between the inhibitor and theenzyme and is therefore independent of the plasma co-factor antithrombinIII. Effective factor Xa inhibition is achieved by administering thecompounds either by oral administration, continuous intravenousinfusion, bolus intravenous administration or any other parenteral routesuch that it achieves the desired effect of preventing the factor Xainduced formation of thrombin from prothrombin.

Anticoagulant therapy is indicated for the treatment and prophylaxis ofa variety of thrombotic conditions of both the venous and arterialvasculature. In the arterial system, abnormal thrombus formation isprimarily associated with arteries of the coronary, cerebral andperipheral vasculature. The diseases associated with thromboticocclusion of these vessels principally include acute myocardialinfarction (AMI), unstable angina, thromboembolism, acute vessel closureassociated with thrombolytic therapy and percutaneous transluminalcoronary angioplasty (PTCA), transient ischemic attacks, stroke,intermittent claudication and bypass grafting of the coronary (CABG) orperipheral arteries. Chronic anticoagulant therapy may also bebeneficial in preventing the vessel luminal narrowing (restenosis) thatoften occurs following PTCA and CABG, and in the maintenance of vascularaccess patency in long-term hemodialysis patients. With respect to thevenous vasculature, pathologic thrombus formation frequently occurs inthe veins of the lower extremities following abdominal, knee and hipsurgery (deep vein thrombosis, DVT). DVT further predisposes the patientto a higher risk of pulmonary thromboembolism. A systemic, disseminatedintravascular coagulopathy (DIC) commonly occurs in both vascularsystems during septic shock, certain viral infections and cancer. Thiscondition is characterized by a rapid consumption of coagulation factorsand their plasma inhibitors resulting in the formation oflife-threatening thrombin throughout the microvasculature of severalorgan systems. The indications discussed above include some, but notall, of the possible clinical situations where anticoagulant therapy iswarranted. Those experienced in this field are well aware of thecircumstances requiring either acute or chronic prophylacticanticoagulant therapy.

These compounds may be used alone or in combination with otherdiagnostic, anticoagulant, antiplatelet or fibrinolytic agents. Forexample adjunctive administration of factor Xa inhibitors with standardheparin, low molecular weight heparin, direct thrombin inhibitors (i.e.hirudin), aspirin, fibrinogen receptor antagonists, streptokinase,urokinase and/or tissue plasminogen activator may result in greaterantithrombotic or thrombolytic efficacy or efficiency. The compoundsdescribed herein may be administered to treat thrombotic complicationsin a variety of animals such as primates including humans, sheep,horses, cattle, pigs, dogs, rats and mice. Inhibition of factor Xa isuseful not only in the anticoagulant therapy of individuals havingthrombotic conditions but is useful whenever inhibition of bloodcoagulation is required such as to prevent coagulation of stored wholeblood and to prevent coagulation in other biological samples for testingor storage. Thus, any factor Xa inhibitor can be added to or contactedwith any medium containing or suspected of containing factor Xa and inwhich it is desired that blood coagulation be inhibited.

In addition to their use in anticoagulant therapy, factor Xa inhibitorsmay find utility in the treatment or prevention of other diseases inwhich the generation of thrombin has been implicated as playing apathologic role. For example, thrombin has been proposed to contributeto the morbidity and mortality of such chronic and degenerative diseasesas arthritis, cancer, atherosclerosis and Alzheimer's disease by virtueof its ability to regulate many different cell types through specificcleavage and activation of a cell surface thrombin receptor. Inhibitionof factor Xa will effectively block thrombin generation and thereforeneutralize any pathologic effects of thrombin on various cell types.

Accordingly, the invention provides a method of inhibiting factor Xacomprising contacting a factor Xa inhibitory amount of a compound offormula I with a composition containing Factor Xa. According to afurther feature of the invention there is provided a method ofinhibiting the formation of thrombin comprising contacting Factor Xainhibitory amount of a compound of formula I with a compositioncontaining Factor Xa.

According to a further feature of the invention there is provided amethod for the treatment of a human or animal patient suffering from, orsubject to, conditions which can be ameliorated by the administration ofan inhibitor of Factor Xa, for example conditions as hereinbeforedescribed, which comprises the administration to the patient of aneffective amount of compound of formula I or a composition containing acompound of formula I. “Effective amount” is meant to describe an amountof compound of the present invention effective in inhibiting Factor Xaand thus producing the desired therapeutic effect.

The present invention also includes within its scope pharmaceuticalformulations which comprise at least one of the compounds of Formula Iin association with a pharmaceutically acceptable carrier or coating.

In practice compounds of the present invention may generally beadministered parenterally, intravenously, subcutaneouslyintramuscularly, colonically, nasally, intraperitoneally, rectally ororally.

The products according to the invention may be presented in formspermitting administration by the most suitable route and the inventionalso relates to pharmaceutical compositions containing at least oneproduct according to the invention which are suitable for use in humanor veterinary medicine. These compositions may be prepared according tothe customary methods, using one or more pharmaceutically acceptableadjuvants or excipients. The adjuvants comprise, inter alia, diluents,sterile aqueous media and the various non-toxic organic solvents. Thecompositions may be presented in the form of tablets, pills, granules,powders, aqueous solutions or suspensions, injectable solutions, elixirsor syrups, and can contain one or more agents chosen from the groupcomprising sweeteners, flavorings, colorings, or stabilizers in order toobtain pharmaceutically acceptable preparations.

The choice of vehicle and the content of active substance in the vehicleare generally determined in accordance with the solubility and chemicalproperties of the product, the particular mode of administration and theprovisions to be observed in pharmaceutical practice. For example,excipients such as lactose, sodium citrate, calcium carbonate, dicalciumphosphate and disintegrating agents such as starch, alginic acids andcertain complex silicates combined with lubricants such as magnesiumstearate, sodium lauryl sulfate and talc may be used for preparingtablets. To prepare a capsule, it is advantageous to use lactose andhigh molecular weight polyethylene glycols. When aqueous suspensions areused they can contain emulsifying agents or agents which facilitatesuspension. Diluents such as sucrose, ethanol, polyethylene glycol,propylene glycol, glycerol and chloroform or mixtures thereof may alsobe used.

For parenteral administration, emulsions, suspensions or solutions ofthe products according to the invention in vegetable oil, for examplesesame oil, groundnut oil or olive oil, or aqueous-organic solutionssuch as water and propylene glycol, injectable organic esters such asethyl oleate, as well as sterile aqueous solutions of thepharmaceutically acceptable salts, are used. The solutions of the saltsof the products according to the invention are especially useful foradministration by intramuscular or subcutaneous injection. The aqueoussolutions, also comprising solutions of the salts in pure distilledwater, may be used for intravenous administration with the proviso thattheir pH is suitably adjusted, that they are judiciously buffered andrendered isotonic with a sufficient quantity of glucose or sodiumchloride and that they are sterilized by heating, irradiation ormicrofiltration.

Suitable compositions containing the compounds of the invention may beprepared by conventional means. For example, compounds of the inventionmay be dissolved or suspended in a suitable carrier for use in anebulizer or a suspension or solution aerosol, or may be absorbed oradsorbed onto a suitable solid carrier for use in a dry powder inhaler.

Solid compositions for rectal administration include suppositoriesformulated in accordance with known methods and containing at least onecompound of formula I.

The percentage of active ingredient in the compositions of the inventionmay be varied, it being necessary that it should constitute a proportionsuch that a suitable dosage shall be obtained. Obviously, several unitdosage forms may be administered at about the same time. The doseemployed will be determined by the physician, and depends upon thedesired therapeutic effect, the route of administration and the durationof the treatment, and the condition of the patient. In the adult, thedoses are generally from about 0.01 to about 100, preferably about 0.01to about 10, mg/kg body weight per day by inhalation, from about 0.01 toabout 100, preferably 0.1 to 70, more especially 0.5 to 10, mg/kg bodyweight per day by oral administration, and from about 0.01 to about 50,preferably 0.01 to 10, mg/kg body weight per day by intravenousadministration. In each particular case, the doses will be determined inaccordance with the factors distinctive to the subject to be treated,such as age, weight, general state of health and other characteristicswhich can influence the efficacy of the medicinal product.

The products according to the invention may be administered asfrequently as necessary in order to obtain the desired therapeuticeffect. Some patients may respond rapidly to a higher or lower dose andmay find much weaker maintenance doses adequate. For other patients, itmay be necessary to have long- term treatments at the rate of 1 to 4doses per day, in accordance with the physiological requirements of eachparticular patient. Generally, the active product may be administeredorally 1 to 4 times per day. It goes without saying that, for otherpatients, it will be necessary to prescribe not more than one or twodoses per day.

The compounds of the present invention may also be formulated for use inconjunction with other therapeutic agents such as agents or inconnection with the application of therapeutic techniques to addresspharmacological conditions which may be ameliorated through theapplication of a compound of formula I, as described herein.

The compounds of the present invention may be used in combination withany anticoagulant, antiplatelet, antithrombotic or fibrinolytic agent.Often patients are concurrently treated prior, during and afterinterventional procedures with agents of these classes either in orderto safely perform the interventional procedure or to prevent deleteriouseffects of thrombus formation. Some examples of classes of agents knownto be anticoagulant, antiplatelet, antithrombotic or profibrinolyticagents include any formulation of heparin, low molecular weightheparins, pentasaccharides, fibrinogen receptor antagonists, thrombininhibitors, Factor Xa inhibitors, or Factor VIIa inhibitors.

The compounds of the present invention may be used in combination withany antihypertensive agent or cholesterol or lipid regulating agent, orconcurrently in the treatment of restenosis, atherosclerosis or highblood pressure. Some examples of agents that are useful in combinationwith a compound according to the invention in the treatment of highblood pressure include compounds of the following classes;beta-blockers, ACE inhibitors, calcium channel antagonists andalpha-receptor antagonists. Some examples of agents that are useful incombination with a compound according to the invention in the treatmentof elevated cholesterol levels or disregulated lipid levels includecompounds known to be HMGCoA reductase inhibitors, compounds of thefibrate class,

It is understood that the present invention includes combinations ofcompounds of the present invention with one or more of theaforementioned therapeutic class agents

Compounds within the scope of the present invention exhibit markedpharmacological activities according to tests described in theliterature and below which tests results are believed to correlate topharmacological activity in humans and other mammals. Enzyme Assays:

The ability of the compounds in the present invention to act asinhibitors of factor Xa, thrombin, trypsin, tissue-plasminogen activator(t-PA), urokinase-plasminogen activator (u-PA), plasmin and activatedprotein C is evaluated by determining the concentration of inhibitorwhich resulted in a 50% loss in enzyme activity (IC50) using purifiedenzymes.

All enzyme assays are carried out at room temperature in 96-wellmicrotiter plates using a final enzyme concentration of I nM. Theconcentrations of factor Xa and thrombin are determined by active sitetitration and the concentrations of all other enzymes are based on theprotein concentration supplied by the manufacturer. Compounds accordingto the invention are dissolved in DMSO, diluted with their respectivebuffers and assayed at a maximal final DMSO concentration of 1.25%.Compound dilutions are added to wells containing buffer and enzyme andpre-equilibrated for between 5 and 30 minutes. The enzyme reactions areinitiated by the addition of substrate and the color developed from thehydrolysis of the peptide-p-nitroanilide substrates is monitoredcontinuously for 5 minutes at 405 nm on a Vmax microplate reader(Molecular Devices). Under these conditions, less than 10% of thesubstrate is utilized in all assays. The initial velocities measured areused to calculate the amount of inhibitor which resulted in a 50%reduction of the control velocity (IC50). The apparent Ki values arethen determined according to the Cheng-Prusoff equation(IC50=Ki[1+[S]/Km]) assuming competitive inhibition kinetics.

An additional in vitro assay may be used to evaluate the potency ofcompounds according to the invention in normal human plasma. Theactivated partial thromboplastin time is a plasma-based clotting assaythat relies on the in situ generation of factor Xa, its assembly intothe prothrombinase complex and the subsequent generation of thrombin andfibrin which ultimately yields the formation of a clot as the assayendpoint. This assay is currently used clinically to monitor the ex vivoeffects of the commonly used anticoagulant drug heparin as well asdirect acting antithrombin agents undergoing clinical evaluation.Therefore, activity in this in vitro assay is considered as a surrogatemarker for in vivo anticoagulant activity.

Human Plasma Based Clotting Assay

Activated partial thromboplastin clotting times are determined induplicate on a MLA Electra 800 instrument. A volume of 100 μl ofcitrated normal human pooled plasma (George King Biomedical) is added toa cuvette containing 100 μl of a compound according to the invention inTris/NaCl buffer (pH 7.5) and placed in the instrument. Following a 3minute warming period the instrument automatically adds 100 μl ofactivated cephaloplastin reagent (Actin, Dade) followed by 100 μl of0.035 M CaCl₂ to initiate the clotting reaction. Clot formation isdetermined spectrophotometrically and measured in seconds Compoundpotency is quantitated as the concentration required to double a controlclotting time measured with human plasma in the absence of the compoundaccording to the invention.

Compounds according to the invention may also be evaluated for their invivo antithrombotic efficacy in two well established animal experimentalmodels of acute vascular thrombosis. A rabbit model of jugular veinthrombosis and a rat model of carotid artery thrombosis are used todemonstrate the antithrombotic activity of these compounds in distinctanimal model paradigms of human venous thrombosis and arterialthrombosis, respectively.

Experimental In Vivo Rabbit Venous Thrombosis Model

This is a well characterized model of fibrin rich venous thrombosis thatis validated in the literature and shown to be sensitive to severalanticoagulant drugs including heparin (Antithrombotic Effect ofRecombinant Truncated Tissue Factor Pathway Inhibitor (TFPI 1-161) inExperimental Venous Thrombosis-a Comparison with Low Molecular WeightHeparin, J. Holst, B. Lindblad, D. Bergqvist, O. Nordfang, P. B.Ostergaard, J. G. L. Petersen, G. Nielsen and U. Hedner. Thrombosis andHaemostasis 71, 214-219 (1994). The purpose of utilizing this model isto evaluate the ability of compounds to prevent the formation of venousthrombi (clots) in vivo generated at a site of injury and partial stasisin the jugular vein.

Male and female New Zealand white rabbits weighing 1.5-2 kg areanesthetized with 35 mg/kg of ketamine and 5 mg/kg xylazine in a volumeof 1 mL/kg (i.m.). The right jugular vein is cannulated for infusion ofanesthetic (ketamine/xylazine 17/2.5 mg/kg/hr at a rate of approximately0.5 mL/hr) and administration of test substances. The right carotidartery is cannulated for recording arterial blood pressure andcollecting blood samples. Body temperature is maintained at 39° C. witha GAYMAR T-PUMP. The left external jugular vein is isolated and all sidebranches along an exposed 2-3 cm of vessel are tied off. The internaljugular vein is cannulated, just above the bifurcation of the commonjugular, and the tip of the cannula is advanced just proximal to thecommon jugular vein. A 1 cm segment of the vein is isolated withnon-traumatic vascular clamps and a relative stenosis is formed by tyinga ligature around the vein with an 18 G needle just below the distalmost clamp. This creates a region of reduced flow and partial stasis atthe injury site. The isolated segment is gently rinsed with saline 2-3times via the cannula in the internal jugular. Thereafter the isolatedsegment is filled with 0.5 mL of 0.5% polyoxyethylene ether (W-1) for 5minutes. W-1 is a detergent which disrupts the endothelial cell liningof the segment, thus providing a thrombogenic surface for initiatingclot formation. After 5 minutes the W-1 is withdrawn from the segment,and the segment is again gently rinsed with saline 2-3 times. Thevascular clamps are then removed, restoring blood flow through thisportion of the vessel. Clot formation is allowed to form and grow for 30minutes after which the vein is cut just below the stenotic ligature andinspected for blood flow (the absence of blood flow is recorded ascomplete occlusion). The entire isolated segment of vein is then ligatedand the formed clot is removed and weighed (wet weight). The effect oftest agents on final clot weights is used as the primary end point.Animals are maintained for an additional thirty minutes to obtain afinal pharmacodynamic measure of anticoagulation. Drug administration isinitiated 15 minutes prior to vascular injury with W-1 and continuedthrough the period of clot formation and maturation. Three blood samples(3 mL ea.) are obtained for evaluation of hemostatic parameters: onejust prior to administration of W-1; a second 30 minutes after removalof the vascular clamps and a third at the termination of the experiment.Antithrombotic efficacy is expressed as a reduction in the final clotweight in preparations treated with a compound according to theinvention relative to vehicle treated control animals.

Experimental In Vivo Rat Arterial Thrombosis Model

The antithrombotic efficacy of factor Xa inhibitors againstplatelet-rich arterial thrombosis may be evaluated using a wellcharacterized rat carotid artery FeCl₂-induced thrombosis model(Superior Activity of a Thromboxane Receptor Antagonist as Compared withAspirin in Rat Models of Arterial and Venous Thrombosis, W. A.Schumacher, C. L. Heran, T. E. Steinbacher, S. Youssef and M. L.Ogletree. Journal of Cardiovascular Pharmacology 22, 526-533 (1993); RatModel of Arterial Thrombosis Induced by Ferric Chloride, K. D. Kurtz, B.W. Main, and G. E. Sandusky. Thrombosis Research, 60, 269-280 (1990);The Effect of Thrombin Inhibition in a Rat Arterial Thrombosis Model, R.J. Broersma, L. W. Kutcher and E. F. Heminger. Thrombosis Research 64,405-412 (1991). This model is widely used to evaluate the antithromboticpotential of a variety of agents including heparin and the direct actingthrombin inhibitors.

Sprague Dawley rats weighing 375-450 g are anesthetized with sodiumpentobarbital (50 mg/kg i.p.). Upon reaching an acceptable level ofanesthesia, the ventral surface of the neck is shaved and prepared foraseptic surgery. Electrocardiogram electrodes are connected and lead IIis monitored throughout the experiment. The right femoral vein andartery are cannulated with PE-50 tubing for administration of a compoundaccording to the invention and for obtaining blood samples andmonitoring blood pressure, respectively. A midline incision is made inthe ventral surface of the neck. The trachea is exposed and intubatedwith PE-240 tubing to ensure airway patency. The right carotid artery isisolated and two 4-0 silk sutures are placed around the vessel tofacilitate instrumentation. An electromagnetic flow probe (0.95-1.0 mmlumen) is placed around the vessel to measure blood flow. Distal to theprobe a 4×4 mm strip of parafilm is placed under the vessel to isolateit from the surrounding muscle bed. After baseline flow measurements aremade, a 2×5 mm strip of filter paper previously saturated in 35% FeCl₂is placed on top of the vessel downstream from the probe for ten minutesand then removed. The FeCl₂ is thought to diffuse into the underlyingsegment of artery and cause deendothelialization resulting in acutethrombus formation. Following application of the FeCI2- soaked filterpaper, blood pressure, carotid artery blood flow and heart rate aremonitored for an observation period of 60 minutes. Following occlusionof the vessel (defined as the attainment of zero X blood flow), or 60minutes after filter paper application if patency is maintained, theartery is ligated proximal and distal to the area of injury and thevessel is excised. The thrombus is removed and weighed immediately andrecorded as the primary end point of the study.

Following surgical instrumentation a control blood sample (B1) is drawn.All blood samples are collected from the arterial catheter and mixedwith sodium citrate to prevent clotting. After each blood sample, thecatheter is flushed with 0.5 mL of 0.9% saline. A compound according tothe invention is administered intravenously (i.v.) starting 5 minutesprior to FeCl₂ application. The time between FeCl₂ application and thetime at which carotid blood flow reached zero is recorded as time toocclusion (TTO). For vessels that did not occlude within 60 minutes, TTOis assigned a value of 60 minutes. Five minutes after application ofFeCl₂, a second blood sample is drawn (B2). After 10 minutes of FeCl₂exposure, the filter paper is removed from the vessel and the animal ismonitored for the remainder of the experiment. Upon reaching zero bloodflow blood a third blood sample is drawn (B3) and the clot is removedand weighed. Template bleeding time measurements are performed on theforelimb toe pads at the same time that blood samples are obtained.Coagulation profiles consisting of activated partial thromboplastin time(APTT) and prothrombin time (PT) are performed on all blood samples. Insome instances a compound according to the invention may be administeredorally. Rats are restrained manually using standard techniques andcompounds are administered by intragastric gavage using a 18 gaugecurved dosing needle (volume of 5 mL/kg). Fifteen minutes afterintragastric dosing, the animal is anesthetized and instrumented asdescribed previously. Experiments are then performed according to theprotocol described above.

By way of example, Compound 184 shows K_(i) values of 27.0 nM, 1.72 μM,and 2.71 μM, in the Factor Xa, trypsin, and thrombin assays,respectively. Compound 45 shows K_(i) values of 94.0 nM, 129 nM, and 477nM, in the Factor Xa, trypsin, and thrombin assays, respectively.Compound 167 shows K_(i) values of 19.0 nM, 46 nM, and 1.228 μM, in theFactor Xa, trypsin, and thrombin assays, respectively.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof.

What is claimed is:
 1. A compound of the formula

is a single or double bond; R_(a) is hydrogen, hydroxy or amino; R₁ andR₂ are hydrogen or taken together are ═NR₉; R₃ is hydrogen, —CO₂R₆,—C(O)R₆, —CONR₆R₆, —CH₂OR₇ or —CH₂SR₇; R₄ is hydrogen, alkyl, Q-alkyl orthioheterocyclyl, or a group of formula

R₅ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl,heterocyclenyl, fused arylcycloalkyl, fused heteroarylcycloalkyl, fusedarylcycloalkenyl, fused heteroarylcycloalkenyl, fused arylheterocyclyl,fused heteroarylheterocyclyl, fused arylheterocyclenyl, fusedheteroarylheterocyclenyl, aryl, fused cycloalkenylaryl, fusedcycloalkylaryl, fused heterocyclylaryl, fused heterocyclenylaryl,heteroaryl, fused cycloalkylheteroaryl, fused cycloalkenylheteroaryl,fused heterocyclenylheteroaryl, fused heterocyclylheteroaryl, aralkyl,heteroaralkyl, aralkenyl, heteroaralkenyl, aralkynyl or heteroaralkynyl;R₆ is hydrogen or lower alkyl; R₇ is hydrogen, lower alkyl, Ar(loweralkyl), lower acyl, aroyl or heteroaroyl; R₈ is hydrogen or lower alkyl;R₉ is hydrogen, R₁₀O₂C—, R₁₀O—, HO—, cyano, R₁₀CO—, HCO—, lower alkyl,nitro, or Y^(1a)Y^(2a)N—; R₁₀ is alkyl, aralkyl, or heteroaralkyl;Y^(1a) and Y^(2a) are independently hydrogen or alkyl; A and B arehydrogen or taken together are a bond; Q is R₇O— or R₇S— or Y¹Y²N—; Y¹and Y² are independently hydrogen, alkyl, aryl, and aralkyl, or one ofY¹ and Y² is acyl or aroyl and the other of Y¹ and Y² is hydrogen,alkyl, aryl, and aralkyl; Ar is aryl or heteroaryl; and n is 0, or 2; ora pharmaceutically acceptable salt thereof, a solvate thereof, orprodrug thereof.
 2. The compound according to claim 1 wherein is asingle bond, or a pharmaceutically acceptable salt thereof, a solvatethereof, or prodrug thereof.
 3. The compound according to claim 1wherein is a double bond, or a pharmaceutically acceptable salt thereof,a solvate thereof, or prodrug thereof.
 4. The compound according toclaim 1 wherein R_(a) is hydrogen, or a pharmaceutically acceptable saltthereof, a solvate thereof, or prodrug thereof.
 5. The compoundaccording to claim 1 wherein R_(a) is hydroxy or amino; more preferredis hydroxy, or a pharmaceutically acceptable salt thereof, a solvatethereof, or prodrug thereof.
 6. The compound according to claim 1wherein R₁ and R₂ taken together are ═NR₉, or a pharmaceuticallyacceptable salt thereof, a solvate thereof, or prodrug thereof.
 7. Thecompound according to claim 1 wherein R₁ and R₂ taken together are ═NH,or a pharmaceutically acceptable salt thereof, a solvate thereof, orprodrug thereof.
 8. The compound according to claim 1 wherein R₃ ishydrogen, or a pharmaceutically acceptable salt thereof, a solvatethereof, or prodrug thereof.
 9. The compound according to claim 1wherein R₃ is —CO₂R₆, —C(O)R₆, —CH₂OR₇ or —CH₂SR₇, or a pharmaceuticallyacceptable salt thereof, a solvate thereof, or prodrug thereof.
 10. Thecompound according to claim 1 wherein R₃ is —CO₂R₆, —CH₂OR₇ or —CH₂SR₇,or a pharmaceutically acceptable salt thereof, a solvate thereof, orprodrug thereof.
 11. The compound according to claim 1 wherein R₃ is—CO₂R₆ or —CH₂OR₇, or a pharmaceutically acceptable salt thereof, asolvate thereof, or prodrug thereof.
 12. The compound according to claim1 wherein R₃ is —CO₂R₆ and R₆ is lower alkyl, or a pharmaceuticallyacceptable salt thereof, a solvate thereof, or prodrug thereof.
 13. Thecompound according to claim 1 wherein R₃ is —CH₂OR₇ or —CH₂SR₇ and R₇ ishydrogen or lower alkyl, or a pharmaceutically acceptable salt thereof,a solvate thereof, or prodrug thereof.
 14. The compound according toclaim 1 wherein R₄ is hydrogen, alkyl or Q-alkyl, or a group of formula

or a pharmaceutically acceptable salt thereof, a solvate thereof, orprodrug thereof.
 15. The compound according to claim 1 wherein R₄ islower alkyl or a group of formula

where A and B are hydrogen and n is 1, or a pharmaceutically acceptablesalt thereof, a solvate thereof, or prodrug thereof.
 16. The compoundaccording to claim 1 wherein R₄ is Q-alkyl, or a pharmaceuticallyacceptable salt thereof, a solvate thereof, or prodrug thereof.
 17. Thecompound according to claim 1 wherein R₄ is R₇O(lower alkyl)-, or apharmaceutically acceptable salt thereof, a solvate thereof, or prodrugthereof.
 18. The compound according to claim 1 wherein R₄ isthioheterocyclyl, or a pharmaceutically acceptable salt thereof, asolvate thereof, or prodrug thereof.
 19. The compound according to claim1 wherein R₅ is alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl,heterocyclenyl, fused arylcycloalkyl, fused heteroarylcycloalkyl, fusedarylcycloalkenyl, fused heteroarylcycloalkenyl, fused arylheterocyclyl,fused heteroarylheterocyclyl, fused arylheterocyclenyl, fusedheteroarylheterocyclenyl, fused cycloalkenylaryl, fused cycloalkylaryl,fused heterocyclylaryl, fused heterocyclenylaryl, fusedcycloalkylheteroaryl, fused cycloalkenylheteroaryl, fusedheterocyclenylheteroaryl, fused heterocyclylheteroaryl, aralkyl,heteroaralkyl, aralkenyl, heteroaralkenyl, aralkynyl or heteroaralkynyl;more preferred is fused cycloalkenylaryl, fused cycloalkylaryl, fusedheterocyclylaryl, fused heterocyclenylaryl, fused cycloalkylheteroaryl,fused cycloalkenylheteroaryl, fused heterocyclenylheteroaryl or fusedheterocyclylheteroaryl, or a pharmaceutically acceptable salt thereof, asolvate thereof, or prodrug thereof.
 20. The compound according to claim1 wherein R₅ is cycloalkyl, heterocyclyl, aralkyl or aralkynyl, or apharmaceutically acceptable salt thereof, a solvate thereof, or prodrugthereof.
 21. The compound according to claim 1 wherein R₅ is aryl orheteroaryl, or a pharmaceutically acceptable salt thereof, a solvatethereof, or prodrug thereof.
 22. The compound according to claim 1wherein R₅ is phenyl, naphthyl, or heteroaryl, or a pharmaceuticallyacceptable salt thereof, a solvate thereof, or prodrug thereof.
 23. Thecompound according to claim 1 wherein R₅ is phenyl substituted phenyl,heteroaryl substituted phenyl, phenyl substituted heteroaryl oroptionally heteroaryl substituted heteroaryl, or a pharmaceuticallyacceptable salt thereof, a solvate thereof, or prodrug thereof.
 24. Thecompound according to claim 1 wherein R₆ is lower alkyl, or apharmaceutically acceptable salt thereof, a solvate thereof, or prodrugthereof.
 25. The compound according to claim 1 wherein Q is R₇O—, or apharmaceutically acceptable salt thereof, a solvate thereof, or prodrugthereof.
 26. The compound according to claim 1 wherein R₇ is hydrogen orlower alkyl, or a pharmaceutically acceptable salt thereof, a solvatethereof, or prodrug thereof.
 27. The compound according to claim 1wherein R₇ is Ar(lower alkyl) or heteroaroyl, or a pharmaceuticallyacceptable salt thereof, a solvate thereof, or prodrug thereof.
 28. Thecompound according to claim 1 wherein R₈ is hydrogen, or apharmaceutically acceptable salt thereof, a solvate thereof, or prodrugthereof.
 29. The compound according to claim 1 wherein R₉ is hydrogen,or a pharmaceutically acceptable salt thereof, a solvate thereof, orprodrug thereof.
 30. The compound according to claim 1 wherein A, B, R₈and R₉ are hydrogen, or a pharmaceutically acceptable salt thereof, asolvate thereof, or prodrug thereof.
 31. The compound according to claim1 wherein R₁₀ is lower alkyl, or a pharmaceutically acceptable saltthereof, a solvate thereof, or prodrug thereof.
 32. The compoundaccording to claim 1 wherein n is 1, or a pharmaceutically acceptablesalt thereof, a solvate thereof, or prodrug thereof.
 33. The compoundaccording to claim 1 wherein the

moiety is in the meta position to the position of attachment of thephenyl moiety to the

a pharmaceutically acceptable salt thereof, a solvate thereof, orprodrug thereof.
 34. The compound according to claim 1 wherein R_(a) ishydroxy or amino, which is in the para position to the

moiety which is in the meta position to the position of attachment ofthe phenyl moiety to the

a pharmaceutically acceptable salt thereof, a solve thereof, or prodrugthereof.
 35. The compound according to claim 34 wherein R_(a) ishydroxy, or a pharmaceutically acceptable salt thereof, a solvatethereof, or prodrug thereof.
 36. The compound according to claim 1wherein Ar is aryl, or a pharmaceutically acceptable salt thereof, asolvate thereof, or prodrug thereof.
 37. The compound according to claim1 wherein Ar is phenyl, or a pharmaceutically acceptable salt thereof, asolvate thereof, or prodrug thereof.
 38. A compound according to claim 1which is:

(Z)-N-[3-(5-Carbamimidoyl-2-hydroxyphenyl)allyl]-4-pyridin-3-ylbenzamide;N-[3-(5-Carbamimidoyl-2-hydroxyphenyl)-propyl]-4-pyridin-3-yl)-benzamideditrifluoroacetate;N-[3-(5-Carbamimidoyl-2-hydroxyphenyl)-propyl]-4-(1-oxy-pyridin-4-yl)-benzamideditrifluoroacetate;N-[3-(5-Carbamimidoyl-2-hydroxyphenyl)-propyl]-4-(6-oxo-1,6-dihydropyridin-3-yl-benzamidetrifluoroacetate;N-[3-(5-Carbamimidoyl-2-hydroxyphenyl)-propyl]-4-(pyridazin-4-yl)benzamideditrifluoroacetate;N-[3-(5-Carbamimidoyl-2-hydroxyphenyl)-propyl]-7-chlorobenzothiophene-2-carboxamidetrifluoroacetate;(E)-N-[3-(5-Carbamimidoyl-2-hydroxy-phenyl)-allyl]-4-(6-methoxy-pyridin-3-yl)-benzamidetrifluoroacetate;(E)-N-[3-(5-Carbamimidoyl-2-hydroxy-phenyl)-allyl]-4-(6-oxo-1,6-dihydro-pyridin-3-yl)-benzamidetrifluoroacetate; (E)-Biphenyl-4-carboxylic acid[3-(5-carbamimidoyl-2-hydroxy-phenyl)-allyl]-amide trifluoroacetate;(E)-N-[3-(5-Carbamimidoyl-2-hydroxy-phenyl)-allyl]-4-pyridin-3-yl-benzamideditrifluoroacetate;(E)-N-[3-(5-Carbamimidoyl-2-hydroxy-phenyl)-allyl]-4-pyridin-4-yl-benzamideditrifluoroacetate; (E)-Biphenyl-3,4′-dicarboxylic acid 3-amide4′-{[3-(5-carbamimidoyl-2-hydroxy-phenyl)-allyl]-amide}trifluoroacetate;(E)-4-tert-Butyl-N-[3-(5-carbamimidoyl-2-hydroxy-phenyl)-allyl]-benzamidetrifluoroacetate;(E)-N-[3-(5-Carbamimidoyl-2-hydroxy-phenyl)-allyl]-4-(3H-imidazol-4-yl)-benzamideditrifluoroacetate; (E)-Biphenyl-4,4′-dicarboxylic acid 4′-amide4-{[3-(5-carbamimidoyl-2-hydroxy-phenyl)-allyl]-amide}trifluoroacetate;(E)-N-[3-(5-Carbamimidoyl-2-hydroxy-phenyl)-allyl]-4-(1H-imidazol-2-yl)-benzamideditrifluoroacetate;(E)-3-Oxo-2,3-dihydro-thieno[3,2-c]pyridazine-6-carboxylic acid[3-(5-carbamimidoyl-2-hydroxy-phenyl)-allyl]-amide trifluoroacetate;(E)-5-Pyridin-2-yl-thiophene-2-carboxylic acid[3-(5-carbamimidoyl-2-hydroxy-phenyl)-allyl]-amide ditrifluoroacetate;Biphenyl-4-carboxylic acid[3-(5-carbamimidoyl-2-hydroxy-phenyl)-propyl]-amide trifluoroacetate;N-[3-(5-Carbamimidoyl-2-hydroxy-phenyl)-propyl]-4-(6-methoxy-pyridin-3-yl)-benzamidetrifluoroacetate; Biphenyl-3,4′-dicarboxylic acid 3-amide4′-{[3-(5-carbamimidoyl-2-hydroxy-phenyl)-propyl]-amide}trifluoroacetate;4-tert-Butyl-N-[3-(5-carbamimidoyl-2-hydroxy-phenyl)-propyl]-benzamidetrifluoroacetate;[3-(5-Carbamimidoyl-2-hydroxy-phenyl)-propyl]-4-(3H-imidazol-4-yl)-benzamideditrifluoroacetate;N-[3-(5-Carbamimidoyl-2-hydroxy-phenyl)-propyl]-4-(1H-imidazol-2-yl)-benzamideditrifluoroacetate; 5-Pyridin-2-yl-thiophene-2-carboxylic acid[3-(5-carbamimidoyl-2-hydroxy-phenyl)-allyl]-amide ditrifluoroacetate;orN-[3-(5-Carbamimidoyl-2-hydroxy-phenyl)-propyl]-4-piperidin-4-yl-benzamideditrifluoroacetate, or a pharmaceutically acceptable salt thereof, asolvate thereof, or prodrug thereof.
 39. A compound according to claim 1which is

or a pharmaceutically acceptable salt thereof, a solvate thereof, orprodrug thereof.
 40. A compound according to claim 1 which is

or a pharmaceutically acceptable salt thereof, a solvate thereof, orprodrug thereof.
 41. A compound according to claim 1 which is

or a pharmaceutically acceptable salt thereof, a solvate thereof, orprodrug thereof.
 42. A compound according to claim 1 which is

or a pharmaceutically acceptable salt thereof, a solvate thereof, orprodrug thereof.
 43. A compound according to claim 1 which is

or a pharmaceutically acceptable salt thereof, a solvate thereof, orprodrug thereof.
 44. A compound according to claim 1 which is

or a pharmaceutically acceptable salt thereof, a solvate thereof, orprodrug thereof.
 45. A compound according to claim 1 which is

or a pharmaceutically acceptable salt thereof, a solvate thereof, orprodrug thereof.
 46. A compound according to claim 1 which is

or a pharmaceutically acceptable salt thereof, a solvate thereof, orprodrug thereof.
 47. A compound according to claim 1 which is

or a pharmaceutically acceptable salt thereof, a solvate thereof, orprodrug thereof.
 48. A compound according to claim 1 which is

or a pharmaceutically acceptable salt thereof, a solvate thereof, orprodrug thereof.
 49. A compound according to claim 1 which is

or a pharmaceutically acceptable salt thereof, a solvate thereof, orprodrug thereof.
 50. A compound according to claim 1 which is

or a pharmaceutically acceptable salt thereof, a solvate thereof, orprodrug thereof.
 51. A compound according to claim 1 which is

or a pharmaceutically acceptable salt thereof, a solvate thereof, orprodrug thereof.
 52. A compound according to claim 1 which is

or a pharmaceutically acceptable salt thereof, a solvate thereof, orprodrug thereof.
 53. A compound according to claim 1 which is2-(R)-(3-Carbamimidoyl-benzyl)-3(R)-[4-(6-oxo-1,6-dihydro-pyridin-3-yl)-benzoylamino]-butyricacid methyl ester trifluoroacetate, or a pharmaceutically acceptablesalt thereof, a solvate thereof, or prodrug thereof.
 54. A compoundaccording to claim 1 which is2(R)-(3-Carbamimidoyl-6-hydroxybenzyl)-3(R)-[4-(6-oxo-1,6-dihydro-pyridin-3-yl)-benzoylamino]-butyricacid methyl ester, or a pharmaceutically acceptable salt thereof, asolvate thereof, or prodrug thereof.
 55. A compound according to claim 1which isN-[3-(5-Carbamimidoyl-2-hydroxyphenyl)-propyl]-4-(6-oxo-1,6-dihydropyridin-3-yl-benzamidetrifluoroacetate, or a pharmaceutically acceptable salt thereof, asolvate thereof, or prodrug thereof.
 56. A compound according to claim 1which is(E)-N-[3-(5-Carbamimidoyl-2-hydroxy-phenyl)-allyl]-4-(6-oxo-1,6-dihydro-pyridin-3-yl)-benzamidetrifluoroacetate, or a pharmaceutically acceptable salt thereof, asolvate thereof, or prodrug thereof.
 57. A compound according to claim 1which is(E)-N-[3-(5-Carbamimidoyl-2-hydroxy-phenyl)-allyl]-4-(1-oxy-pyridin-4-yl)-benzamideditrifluoroacetate, or a pharmaceutically acceptable salt thereof, asolvate thereof, or prodrug thereof.
 58. A pharmaceutical compositioncomprising a pharmaceutically acceptable amount of the compoundaccording to claim 1 and a pharmaceutically acceptable carrier.
 59. Amethod for treating a patient suffering from a disease state capable ofbeing modulated by inhibiting production of Factor Xa comprisingadministering to said patient a pharmaceutically effective amount of thecompound according to claim
 1. 60. A method of inhibiting factor Xacomprising contacting a Factor Xa inhibitory amount of a compoundaccording to claim 1 with a composition containing Factor Xa.
 61. Amethod of inhibiting the formation of thrombin comprising contactingFactor Xa inhibitory amount of a compound according to claim 1 with acomposition containing Factor Xa.